Therapeutic treatment methods

ABSTRACT

The invention relates to the use of compounds to ameliorate or treat a condition such as a cystic fibrosis, neutropenia or other exemplified conditions. Exemplary compounds that can be used include 3β-hydroxy-17β-aminoandrost-5-ene, 3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene, 3α-hydroxy-16α-fluoro-17β-aminoandrost-5-ene, 3β-hydroxy-16β-fluoro-17β-aminoandrost-5-ene, 1α,3β-dihydroxy-4α-fluoroandrost-5-ene-17-one, 1α,3β,17β-trihydroxy-4α-fluoroandrost-5-ene, 1β,3β-dihydroxy-6α-bromoandrost-5-ene, 1α-fluoro-3β,12α-dihydroxyandrost-5-ene-17-one, 1α-fluoro-3β,4α-dihydroxyandrost-5-ene and 4α-fluoro-3β,6α,17β-trihydroxyandrostane.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation and claims priority under 35 USC §120 of U.S. application Ser. No. 10/728,400 filed Dec. 5, 2003 nowabandoned which is a continuation-in-part of U.S. application Ser. No.10/651,515, filed Aug. 28, 2003, now abandoned which claims benefitunder 35 USC § 119(e) of abandoned U.S. provisional application Ser. No.60/407,146, filed Aug. 28, 2002, abandoned U.S. provisional applicationSer. No. 60/408,332, filed Sep. 4, 2002, and abandoned U.S. provisionalapplication Ser. No. 60/479,257, filed Jun. 17, 2003, all of which areincorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to methods to use compounds, such as3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-16β-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-17β-aminoandrost-5-ene,1α,3β-dihydroxy-4α-fluoroandrost-5-ene,1α,3β,17β-trihydroxy-4α-fluoroandrost-5-ene,1β,3β-dihydroxy-6-bromoandrost-5-ene-17-one,1α-fluoro-3β,12α-dihydroxyandrost-5-ene-17-one,1α-fluoro-3β,4α-dihydroxyandrost-5-ene and4α-fluoro-3β,6α,17β-trihydroxyandrostane to treat, ameliorate or preventneutropenia, cystic fibrosis conditions or other pathological or diseaseconditions or their symptoms.

BACKGROUND

Immune dysregulation can be a component of many pathological diseases orconditions. Such dysregulation may be a factor that favors theestablishment, maintenance or progression of these diseases orconditions. Deficient immune responses or immune suppression can enhancea mammal's susceptibility to infection or to the development of cancer.Conversely, excessive or inappropriate immune responses can play a rolein the establishment or progression of unwanted inflammation orautoimmune conditions. It would thus be advantageous to utilize agentsthat can modulate immune responses and to at least partially reverseimmune dysregulation when such dysregulation is a component of a givenpathological condition. Some agents are known that can ameliorate someaspects of immune dysregulation, but typically such agents have theirown unwanted effects on either the host's immune system or other organsor tissues. Agents such as glucocorticoid steroids have been used toreduce unwanted inflammation in a number of clinical conditions, butsuch compounds often have serious limitations, such as inducing immunesuppression or causing unwanted mood changes.

Human and mammalian immune responses to infections or other conditionsare often characterized by responses mediated by different immuneeffector cell populations. In some situations, helper T cells designatedTh1 in the murine system, facilitate immune effector functions that aretypically dominated by cell-mediated responses. In other cases, helper Tcells designated Th2 cells facilitate immune effector functions that aretypically dominated by humoral responses. A vigorous Th1 response isusually desirable to help clear infections or to slow the progression ofan infection. When a subject's immune response is biased to, ordominated by, a Th2-type response, the cytokines associated with the Th2response tend to suppress the immune system's capacity to mount avigorous Th1 response at the same time. The converse is also generallytrue. When mammalian immune responses begin to result in an increasingTh1 response, Th2 responses tend to weaken. Insufficient Th1 responsesmay be associated with progression of some infections or otherconditions, see, e.g., M. Clerici and G. M. Shearer, Immunol. Today14:107-111, 1993; M. Clerici and G. M. Shearer, Immunol. Today15:575-581, 1994.

Methods to make and use 3β-hydroxyandrost-5-ene-17-one(dehydroepiandrosterone) and certain other steroids and their biologicalproperties have been described, see, e.g., U.S. Pat. Nos. 2,833,793,2,911,418, 3,148,198, 3,471,480, 3,976,691, 4,000,125, 4,083,969,4,268,441, 4,427,649, 4,542,129, 4,666,898, 4,956,355, 5,001,119,5,043,165, 5,077,284, 5,028,631, 5,110,810, 5,157,031, 5,162,198,5,175,154, 5,277,907, 5,292,730, 5,296,481, 5,372,996, 5,387,583,5,407,684, 5,424,463, 5,461,042, 5,478,566, 5,506,223, 5,518,725,5,527,788, 5,527,789, 5,532,230, 5,559,107, 5,562,910, 5,583,126,5,585,371, 5,587,369, 5,591,736, 5,593,981, 5,629,295, 5,610,150,5,635,496, 5,641,766, 5,641,768, 5,656,621, 5,660,835, 5,686,438,5,696,106, 5,700,793, 5,707,983, 5,709,878, 5,710,143, 5,714,481,5,728,688, 5,736,537, 5,744,462, 5,753,237, 5,756,482, 5,776,921,5,776,923, 5,780,460, 5,795,880, 5,798,347, 5,798,348, 5,804,576,5,807,848, 5,807,849, 5,811,418, 5,824,313, 5,824,668, 5,824,671,5,827,841, 5,837,269, 5,837,700, 5,843,932, 5,846,963, 5,859,000,5,872,114, 5,872,147, 5,162,198, 5,206,008, 5,292,730, 5,407,684,5,461,042, 5,461,768, 5,478,566, 5,585,371, 5,635,496, 5,641,766,5,837,269, 5,885,977, 5,846,963, 5,919,465, 5,869,090, 5,863,910,5,856,340, 5,804,576, 5,714,481, 6,150,336, 4,978,532, 4,898,694,4,542,129, 3,711,606, 3,710,795, 3,189,597, 3,137,710 and 2,531,441;German patent numbers 2,035,738 and 2,705,917; PCT publication numbersWO 95/21617, WO 97/38695, WO 97/48367, WO 98/05338, WO 98/50040, WO98/50041, WO 98/58650, WO 00/32176, WO 00/32177, WO 00/32201, WO00/35472, WO 00/56757, WO 01/30802, WO 93/20696, WO 99/25333, WO01/30802, WO 01/23405, WO 02/28880, WO 02/69977 and WO 03/039554;European publication numbers 0020029, 0090736, 0133995, 0934745 and0637203; E. R. Glazier, J. Org. Chem. 1962 27:2937-2938, Ben-David, etal., Proc. Soc. Expt. Biol. Med. 1967 125:1136-1140, Coleman et al.,Diabetes 1982 31:830, Oertel, et al., J. Steroid Biochem. 19723:493-496, Pashko, et al., Carcinogenesis 1981 2:717-721, Schwartz etal., Nutr. Cancer 1981 3:46-53, Dyner et al., J. Acquired ImmuneDeficiency Syndromes 1993 6:459-465, M. H. Whitnall et al., Int'l. J.Immunopharmacology 2000 22:1-14, I. Porsova-Dutoit et al., PhysiologicalRes. 2000 49 (Suppl. 1):S43-S56, R. L. Jesse et al., Ann. N.Y. Acad.Sci. 1995 774:281-290, C. Chavis et al., Steroids 1982 39:129-147, M.Numazawa and Y. Osawa Steroids 1981 38:149-159, G. Flouret et al., J.Med. Chem. 1972 15:1281-1283 and A. A. Afanasii and Y. A. Titov, TotalSteroid Synthesis, Plenum Press, New York, 1970, see, e.g., p 1-304.

U.S. Pat. Nos. 4,908,358 and 4,902,681 describe the capacity ofcompounds such as 5α-pregnan-3,20-dione, cortexolone,17-hydroxyprogesterone and 16α-methylprogesterone to inhibit theclearance of antibody-coated cells from circulation in disorders such asimmune thrombocytopenic purpura or immune hemolytic anemia.

U.S. Pat. Nos. 5,532,230, 5,686,438, 5,753,640 and 5,811,418 and J.Bratt and M. Heimburger, Scand. J. Rheumatol. 1999 28:308-313 describethe capacity of compounds such as prednisolone, and3β-hydroxyandrost-5-ene-17-one to limit tissue damage in ischemictissues by inhibiting adhesion of cells such as neutrophils toendothelial cells or to treat pulmonary hypertension.

U.S. Pat. No. 5,859,000 describes the capacity compounds such as3β-hydroxyandrost-5-ene-17-one to reduce mast cell mediated allergicreactions.

U.S. Pat. Nos. 5,763,433 and 6,372,732 and PCT publication WO 96/35428describe the capacity of certain androstane and androstene compoundssuch as 3β-hydroxyandrost-5-ene-17-one to treat certain immune disorderconditions such as systemic lupus erythematosus.

U.S. Pat. Nos. 5,925,630, 5,939,545 and 5,962,443 describe the capacityof 19-nur-pregnane steroids, 3α-hydroxy-5α-pregnan-20-one and relatedsteroids to modulate certain neurological activities such ashypothalamic function and GABA receptor activity.

Other biological effects and/or metabolic conversions of steroidcompounds have been described, e.g., Batta et al., J. Biol. Chem. 198625:127-133, Belli et al., Liver 1991 11:162-169, Bhattacharjee et al.,Anal. Biochem. 1992 201:233-236, Blake et al., Int. J. Peptide ProteinRes. 1982 20:97-101, 1986 25:127-133, Bonaventura, Am. J. Obstet.Gynecol. 1978 131:403-409, Bucala et al., J. Steroid Biochem. 198625:127-133, Carey et al., Biochem. 1981 20:3637-3648, Chen et al.,Carcinogenesis 1999 20:249-254, Chen et al., Carcinogenesis 199819:2187-2193, Chow et al., Antisense Res. Dev. 1994 4:81-86, Citro etal., Dis. Colon Rectum 1994 37(2 Suppl):S127-S132, Cleary, Proc. Soc.Exp. Biol. Med. 1991 196:8-16, Cleary, Int. J. Biochem. 1990 22:205-210,Crawford et al., Lab. Invest. 1994 71:42-51, Danenberg et al.,Antimicrob. Agents Chemother. 1992 36:2275-2279, Dotzlaw et al., CancerRes. 1999 59:529-532, Falany et al., J. Steroid Biochem. Mol. Biol. 199448:369-375, Faredin et al., J. Investigative Dermatol. 1969 52:357-361,Galigniana et al., Mol. Pharmacol. 1999 55:317-323, Goto et al., J.Chromatogr. 1983 276:289-300, Grenot Biochem. 1992 31:7609-7621,Hofbauer et al., Life Sci. 1999 64:671-679, Huijghebaert et al., J.Lipid Res. 1986 27:742-752, Hurd et al., Oncogene 1999 18:1067-1072,Iida et al., J. Lipid Res. 1995 36:628-638, Jellinck et al., Steroids1967 10:329-346, Jonsson et al., J. Pediatr. Gastroenterol. Nutr. 199520:394-402, Kalimi et al, Mol. Cell. Biochem. 1994 131:99-108, Kramer etal., J. Biol. Chem. 1994 269:10621-10627, LaRochelle et al., Steroids1984 43: 209-217, Liao et al., Carcinogenesis 1998 19:2173-2180,Lillienau et al., J. Clin. Invest. 1992 89:420-431, Loria,Psychoneuroendocrinology 1997 22:S103-S108, Luscher et al Mol. Immunol.1983 20:1099-1105, Manna et al., J. Biol. Chem. 1999 274:5909-5918,Marschall et al., J. Biol. Chem. 1989 264:12989-12993, Medh et al.,Cancer Res. 1998 15:3684-3693, Mohan et al., Steroids 1992 57:244-247,Munoz de Toro et al., J. Steroid Biochem. Mol. Biol. 1998 67:333-339,Padgett et al., J. Neuroimmunol. 1998 84:61, Padgett et al., Ann. N.Y.Acad. Sci. 1995 774:323, Padgett et al., J. Immunol. 1994 153:1544-1552,Pashko et al., Carcinogenesis 1984 5:463-466, Pashko et al.,Carcinogenesis 1981 2:717, Petrylak et al., J. Clin. Oncology 199917:958-967, Podesta et al., Steroids 1996 61:622-626, Regelson et al.,Ann. N.Y. Acad. Sci. 1994 719:564, Schmassmann et al., Gastroenterology1993 104:1171-1181, Schmassmann et al., Hepatology 1990 11:989-996,Schreiber et al., Lancet 353:459-461, Schreiber, Neth. J. Med. 199853:S24-31, Schwartz et al., Cancer Res. 1988 48:4817, Shahidi et al.,Biochem. Biophys. Res. Commun. 1999 254:559-565, Steer et al., Ann.Rheum. Dis. 1998 57:732-737, Suzuki et al., Steroids 1998 63:672-677,Suzuki et al., Steroids 1996 61:296-301, Swaan et al., BioconjugateChem. 1997 8:520-525, Tang et al, Anticancer Drug Res. 1998 13:815-824,Thomas et al., J. Steroid Biochem. 1986 25:103-108, Utsumi et al.,Cancer Res. 1999 59:377-381, Vanden Heuvel, J. Nutr. 1999 129(2SSuppl.):575S-580S, Wang et al., Endocrinology 1998 139:3903-3912, Wonget al., J. Biol. Chem. 1999 274:5443-5453, Xie et al., Endocrinology1999 140:219-227, Yen et al., Lipids 1977 12:409-413, Zackheim et al.,Arch. Dermatology 1998 134:949-954, Zhang et al., Biochim. Biophys. Acta1991 1096:179-186, Zhu et al., Carcinogenesis 1988 19:2101-2106.

Some proteins such as interleukin-6 (“IL-6”), erythropoietin (“EPO”) andthrombopoietin (“TPO”) have been examined for their capacity to enhancevarious aspects hematopoiesis, e.g., Hematology—Basic Principles andPractice, 3^(rd) edition, R. Hoffman, E. J. Benz Jr. et al., editors,Churchill Livingstone, N.Y., 2000 (see, e.g., Chapter 14 at pages154-202), O. J. Borge et al., Blood 1996 88:2859-2870, M. Cremer et al.,Ann. Hematol. 1999 78:401-407, Y. Sasaki et al., Blood 199994:1952-1960, U.S. Pat. No. 5,879,673. Recombinant IL-6 was shown inmodel systems to affect platelet counts in peripheral circulation, e.g.,Stahl et al., Blood 1991 78:1467-1475, although significant toxicitiesare associated with its administration to humans, e.g., Andus et al.,FEBS Lett. 1987 221:18, J. Gauldie et al., P.N.A.S. U.S.A. 198784:7251-7255, T. Geiger et al., Eur. J. Immunol. 1988 18:717-721. TheIL-6 molecule has been described in detail, e.g., publication no. WO88/00206. Administration of proteins is typically expensive, givenfactors such as the complexity of producing pharmaceutical gradematerial.

There is a current need for cost-effective pharmaceutical agents andtreatment methods for treating various immune dysregulation conditions.The invention provides compounds that can be used in such treatments totreat or ameliorate one or more aspects of immune dysregulationconditions. The compounds can provide surprisingly unexpected beneficialeffects, e.g., in preventing or reducing neutropenia in subjects such asmammals or primates. Such agents can be used to treat autoimmune orinflammation conditions, immune suppression conditions, infections,blood cell deficiencies and other described conditions. The agents andmethods are useful to ameliorate these conditions or one or moresymptoms associated with any of these conditions. The use of theseagents can be combined with one or more conventional treatments forthese disorders.

DESCRIPTION OF THE INVENTION

Summary of invention embodiments. In principal embodiments the inventionprovides therapeutic treatment methods.

The methods include a method to prevent, treat, ameliorate or slow theprogression of cystic fibrosis, sickle cell disease, neutropenia orthrombocytpoenia in a subject, or to treat a symptom of the cysticfibrosis, sickle cell disease, neutropenia or thrombocytopenia,comprising administering to a subject, or delivering to the subject'stissues, an effective amount of a formula 1 compound having thestructure 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14

or a metabolic precursor or a metabolite thereof, wherein

R¹⁰ moieties at the 5 (if present), 8, 9 and 14 positions respectivelyare in the α,α,α,α, α,α,α,β, α,α,β,α, α,β,α,α, β,α,α,α, α,α,β,β,α,β,α,β, β,α,α,β, β,α,β,α, β,β,α,α, α,β,β,α, α,β,β,β, β,α,β,β, β,β,α,β,β,β,β,α or β,β,β,β configurations,

wherein R^(10A), R^(10B), R^(10C), R^(10D) and R^(10E) respectively arein the α,α, α,β, β,α or β,β configurations,

wherein, each R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰, R^(10A), R^(10B), R^(10C),R^(10D) and R^(10E) independently are —H, —OH, —OR^(PR), —SR^(PR),—N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN, —NO₂, —NH₂, —COOH,—OSO₃H, —OPO₃H, an ester, a thioester, a thionoester, a phosphoester, aphosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, asulfate ester, an amide, an amino acid, a peptide, an ether, athioether, an acyl group, a thioacyl group, a carbonate, a carbamate, ahalogen, an optionally substituted alkyl group, an optionallysubstituted alkenyl group, an optionally substituted alkynyl group, anoptionally substituted aryl moiety, an optionally substituted heteroarylmoiety, an optionally substituted heterocycle, an optionally substitutedmonosaccharide, an optionally substituted oligosaccharide, a nucleoside,a nucleotide, an oligonucleotide, a polymer, or,

one more of R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰, R^(10A), R^(10B), R^(10C),R^(10D) and R^(10E) are ═O, ═S, ═N—OH, ═CH₂, ═CH—CH₃, or anindependently selected spiro ring and the hydrogen atom or the secondvariable group that is bonded to the same carbon atom is absent, or,

one or more of two adjacent R¹-R⁶, R¹⁰, R^(10A), R^(10B), R^(10C),R^(10D) and R^(10E) comprise an independently selected epoxide, acetal,a thioacetal, ketal or thioketal;

R⁷ is —C(R¹⁰)₂—, —C(R¹⁰)₂—C(R¹⁰)₂—, —C(R¹⁰)₂—C(R¹⁰)₂—C(R¹⁰)₂—,—C(R¹⁰)₂—O—C(R¹⁰)₂—, —C(R¹⁰)₂—S—C(R¹⁰)₂—, —C(R¹⁰)₂—NR^(PR)—C(R¹⁰)₂—,—O—, —O—C(R¹⁰)₂—, —S—, —S—C(R¹⁰)₂—, —NR^(PR)— or —NR^(PR)—C(R¹⁰)₂—;

R⁸ and R⁹ independently are —C(R¹⁰)₂—, —C(R¹⁰)₂—C(R¹⁰)₂—, —O—,—O—C(R¹⁰)₂—, —S—, —S—C(R¹⁰)₂—, —NR^(PR)— or —NR^(PR)—C(R¹⁰)₂—, or one orboth of R³ or R⁹ independently are absent, leaving a 5-membered ring;

R¹³ independently is C₁₋₆ alkyl; and

R^(PR) independently is —H or a protecting group. In typicalembodiments, one or two of R^(10A), R^(10B), R^(10C), R^(10D) andR^(10E) are not hydrogen or one R⁴ is —NH₂, an optionally substitutedamine, —N(R^(PR))², ═NOH, ═NO-optionally substituted alkyl, an amide oran N-linked amino acid.

Other embodiments include (1) certain new formula 1 compounds, which arenew chemical entities, (2) compositions that comprise a formula 1compound and another compound or an excipient, (3) formulations thatcomprise a formula 1 compound and 1, 2, 3, 4, 5, 6 or more excipients.The formulations can be designed for human pharmaceutical use or theycan be suitable for veterinary use. Therapeutic use embodiments include(1) use of a formula 1 compound for the preparation of a medicament and(2) use of a formula 1 compound for the preparation of a medicament forthe prophylaxis or treatment of a condition or symptom disclosed herein.

Other embodiments are as described elsewhere in the specificationincluding the claims.

Definitions. As used herein and unless otherwise stated or implied bycontext, terms that are used herein have the meanings defined below.Unless otherwise contraindicated or implied, e.g., by including mutuallyexclusive elements or options, in these definitions and throughout thisspecification, the terms “a” and “an” mean one or more and the term “or”means and/or.

Reference to an androstane compound, e.g., 3β, 16α,17β-trihydroxyandrostane, means that the hydrogen atom at the 5-positionis in the α-configuration. For androstanes with hydrogen in theβ-configuration, the compound name will specify this configuration,e.g., 3β, 16α, 17β-trihydroxy-5β-androstane.

An “invention formulation”, “formulation”, “pharmaceutical formulation”or the like means a composition that one can administer to a subject,e.g., human, mammal or other animal, without further manipulations thatchange the ingredients or the ingredient proportions that are present.Formulations will typically comprise a single formula 1 compound and oneor more excipients. Formulations are suitable for human or veterinaryapplications and would typically have expected characteristics for theformulation, e.g., parenteral formulations for human use would usuallybe sterile and stored in a suitable closed container.

When referring to mixtures that contain a formula 1 compound, an“invention composition”, “composition” or the like means a composition,that is a formulation or that can be an intermediate one can use, e.g.,to make a formulation or a formula 1 compound. Compositions also includeother types of mixtures, e.g., (1) reagents for assays or cells that areoptionally contacted with a formula 1 compound or mixtures of compoundsand (2) compounds used to make a formula 1 compound or by-products offormula 1 compound synthesis or analysis. Invention compositions includecompositions where further processing may be required before it is aformulation, e.g., mixing or addition of a desired amount of anexcipient.

Phrases such as “administration of a compound of formula 1”, “treatmentwith a formula 1 compound”, “use of a formula 1 compound” or similarterms mean that the compound(s) is administered to, contacted with ordelivered to, the subject or to the subject's cells or tissues in vitroor in vivo by one or more suitable methods, e.g., in vivo delivery canbe by an oral, topical, subcutaneous, parenteral, buccal or sublingualroute.

Expressions such as “a formula 1 compound(s)”, “a formula 1 compound”and the like mean invention compositions or formulations where one ormore than one formula 1 compound is present, e.g., in a composition, oris used in the disclosed method, typically 1, 2, 3 or 4, usually 1. Anyreference to a “formula 1 compound”, “one or more compounds of formula1” or the like means that the formula 1 compound can have the formula 2structure or any other structure disclosed herein that is within thedefinition of formula 1 compounds. The phrase formula 1 compound orformula 1 compound(s) is sometimes abbreviated as “F1C” or “F1C(s)” andformula 1 compounds may be abbreviated as “F1Cs”.

Reference to subject matter “as disclosed herein” such as a “therapeutictreatment or agent as disclosed herein”, a “dosing protocol as disclosedherein” or a “clinical condition or symptom as disclosed herein” or thelike means a treatment, agent, protocol, condition, symptom or the likethat is described herein or in any reference that is cited herein.

An “excipient”, “carrier”, “pharmaceutically acceptable excipient”,“pharmaceutically acceptable carrier” or similar terms mean one or morecomponent(s) or ingredient(s) that is acceptable in the sense of beingcompatible with the other ingredients of invention compositions orformulations and not overly deleterious to the patient, animal, tissuesor cells to which the F1C, composition or formulation is to beadministered.

A “subject” means a human or animal. Usually the animal is a mammal orvertebrate such as a primate, rodent, lagomorph, domestic animal or gameanimal. Primates include chimpanzees, cynomologous monkeys, spidermonkeys, and macaques, e.g., Rhesus or Pan. Rodents and lagomorphsinclude mice, rats, woodchucks, ferrets, rabbits and hamsters. Domesticand game animals include cows, horses, pigs, sheep, deer, bison,buffalo, mink, felines, e.g., domestic cat, canines, e.g., dog, wolf andfox, avian species, e.g., chicken, turkey, emu and ostrich, and fish,e.g., trout, catfish and salmon. Subject includes any subset of theforegoing, e.g., all of the above, but excluding one or more groups orspecies such as humans, primates or rodents. Other subsets of subjectsinclude subjects of a given species or group of species of varying ages,e.g., young humans, e.g., about 1 week of age to about 9 years of age,adolescent humans, e.g., about 10-19 years of age, adult humans, e.g.,about 20-100 years of age, and mature adult or elderly humans, e.g., atleast about 55 years of age, at least about 60 years of age, at leastabout 65 years of age or a range of ages such as about 60-100 years ofage. Thus, as used herein, prevention or treatment of a disease,condition or symptom may include or exclude any subset of subjects thatare grouped by age.

The terms “effective amount”, “effective dose” or the like withreference to a F1C(s) mean an amount of the F1C(s) that is sufficient toelicit a desired response, e.g., detectable restoration of normal immuneresponsiveness in an immunodeficient subject to which it isadministered, e.g., a human, or to detectable modulation or ameliorationof an immune or cellular parameter or a clinical condition or symptom.An effective amount, e.g., for human therapeutic use, may be a singledose or two or more subdoses of a F1C administered in one day, or it maybe administered as multiple doses over a period of time, e.g., over 1,2, 3, 4 or about 7 days to about 1 year.

Terms such as “use”, “treat”, “treatment”, “address” or the like in thecontext of using the F1Cs in the treatment methods or other methodsdisclosed herein mean that a F1C is administered to a subject, deliveredto the subject's tissues or contacted with tissues, cells or cell freesystems in vivo or in vitro, e.g., as described herein or a referencecited herein. Typically such use or treatment results in, e.g., (1)detectable improvement in or amelioration of the condition or symptombeing treated, (2) detectable modulation in the activity, level ornumbers of a relevant biomolecule, therapeutic immune cell population ora pathological cell population, (3) slowing of the progression of acondition or delaying its onset, or reduction of the severity of asymptom(s) of the condition or (4) another detectable response asdescribed herein. Any such amelioration may be transient, e.g., lastingfor at least a few, e.g., about 1 to 24, hours or days, e.g., about 1,2, 3, 4, 5, 6 or 7 days, or amelioration may be prolonged, e.g., lastingabout 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 24, 26,28, 35, 42, 49, 56 to about 60 days or more, or amelioration may bepermanent. A treatment may slow the progression of a disease or symptomor it may reduce the severity thereof, e.g., onset of a disease or asymptom may be delayed in at least some subjects for about 1-24 hours,about 2-10 days, about 2-30 days or for about 1-5 years compared tosubjects who are not treated with sufficient amounts of the F1C. Thus, aF1C use or treatment typically results in detectable modulation in arelevant immune parameter such as modulation of the level, activity orrelative amount of a target effector or suppressor immune cellpopulation, interleukin, cytokine, chemokine, immunoglobulin compared toa suitable control, e.g., untreated. A F1C treatment can also causemodulation of the level or activity of a relevant transcription factor,enzyme, cell biological activity or level or activity of the etiologicalagent of the disease such as a pathogen, tumor cell or autoreactiveimmune cell subset. A treatment with a F1C may be used to delay orprevent the onset of a disease, symptom or complication or to ameliorateor slow the progression of a preexisting disease, condition, symptom orcomplication, or to facilitate elimination of a disease, condition,symptom or complication.

“Ameliorate”, “amelioration”, “improvement” or the like means adetectable improvement or a detectable change consistent withimprovement occurs in a subject or in at least a minority of subjects,e.g., in at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%,70%, 75%, 80%, 85%, 90%, 95%, 98%, 100% or in a range about between anytwo of these values. Such improvement or change may be observed intreated subjects as compared to subjects not treated with a F1C, wherethe untreated subjects have, or are subject to developing, the same orsimilar disease, condition, symptom or the like. Amelioration of adisease, condition, symptom or assay parameter may be determinedsubjectively or objectively, e.g., self assessment by a subject(s), by aclinician's assessment or by conducting an appropriate assay ormeasurement, including, e.g., a quality of life assessment, a slowedprogression of a disease(s) or condition(s), a reduced severity of adisease(s) or condition(s), or a suitable assay(s) for the level oractivity(ies) of a biomolecule(s), cell(s) or by detection of cellmigration within a subject. Amelioration may be transient, prolonged orpermanent or it may be variable at relevant times during or after a F1Cis administered to a subject or is used in an assay or other methoddescribed herein or a cited reference, e.g., within about 1 hour of theadministration or use of a F1C to about 3, 6, 9 months or more after asubject(s) has received a F1C.

The “modulation” of, e.g., a symptom, level or biological activity of amolecule, replication of a pathogen, cellular response, cellularactivity or the like, means that the cell, level or activity, or thelike is detectably increased or decreased. Such increase or decrease maybe observed in treated subjects as compared to subjects not treated witha F1C, where the untreated subjects have, or are subject to developing,the same or similar disease, condition, symptom or the like. Suchincreases or decreases may be at least about 2%, 5%, 10%, 15%, 20%, 25%,30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100%, 150%, 200%,250%, 300%, 400%, 500%, 1000% or more or about within any range aboutbetween any two of these values. Modulation may be determinedsubjectively or objectively, e.g., by the subject's self assessment, bya clinician's assessment or by conducting an appropriate assay ormeasurement, including, e.g., quality of life assessments or suitableassays for the level or activity of molecules, cells or cell migrationwithin a subject. Modulation may be transient, prolonged or permanent orit may be variable at relevant times during or after a F1C isadministered to a subject or is used in an assay or other methoddescribed herein or a cited reference, e.g., within about 1 hour of theadministration or use of a F1C to about 3, 6, 9 months or more after asubject(s) has received a F1C.

Terms such as “antigen”, “immunogen”, “antigenic fragment” or the likemean a molecule that comprises one or more epitopes that are capable ofstimulating a subject's immune system to make, e.g., a secretory,humoral or cellular antigen-specific response against the antigen,immunogen or fragment. Antigenic fragments are synthetic or naturalderivatives of natural or intact antigens or immunogens that retain atleast a detectable capacity, e.g., at least about 10%, 20%, 30%, 40%,50% or more of the native antigen's antigenic capacity, to stimulate asubject's immune system in a desired manner.

“Vaccine composition”, “vaccine” or similar terms mean an agent suitablefor stimulating a subject's immune system to ameliorate a currentcondition or to protect against or to reduce present or future harm orinfection, e.g., reduced tumor cell proliferation or survival, reducedpathogen replication or spread in a subject or a detectably reducedunwanted symptom(s) associated with a condition. Vaccines may modulate,typically detectably enhance, humoral, cell mediated or innate immuneresponses.

“Immunization” means the process of inducing a detectable and continuingmoderate or high level of antibody or cellular immune response that isdirected against an antigen to which the subject has been exposed. Suchresponses are typically detectably maintained for at least about 3-48months or more.

At various locations in the present disclosure, e.g., in any disclosedembodiments or in the claims, reference is made to compounds,compositions, formulations, or methods that “comprise” one or morespecified components, elements or steps. Invention embodiments alsospecifically include those compounds, compositions, formulations ormethods that are or that consist of or that consist essentially of thosespecified components, elements or steps. The terms “comprising”,“consist of” and “consist essentially of” have their normally acceptedmeanings under U.S. patent law. For example, disclosed compositions ormethods that “comprise” a component or step are open and they include orread on those compositions or methods plus an additional component(s) orstep(s). Similarly, disclosed compositions or methods that “consist of”a component or step are closed and they would not include or read onthose compositions or methods having appreciable amounts of anadditional component(s) or an additional step(s).

“Alkyl” as used here means linked normal, secondary, tertiary or cycliccarbon atoms, i.e., linear, branched, cyclic or any combination thereof.Alkyl moieties, as used herein, may be saturated, or unsaturated, i.e.,the moiety may comprise one, two, three or more independently selecteddouble bonds or triple bonds. Unsaturated alkyl moieties includemoieties as described for alkenyl and alkynyl moieties described below.The number of carbon atoms in an alkyl group or moiety can vary andtypically is 1 to about 50, e.g., about 1-30 or about 1-20, unlessotherwise specified, e.g., C₁₋₈ alkyl or C1-C8 alkyl means an alkylmoiety containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. When an alkylgroup is specified, species may include methyl, ethyl, 1-propyl(n-propyl), 2-propyl (i-propyl, —CH(CH₃)₂), 1-butyl (n-butyl),2-methyl-1-propyl (i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂),2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂),3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl, 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl(—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃),3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl(—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂),2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl(—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃), cyclopropyl(—CH<CH₂CH₂), cyclobutyl (—CH<CH₂CH₂CH₂), cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, —(CH₂)_(n)—(CHCH₃)_(m)—(CH₂)_(o)—CH₃,—(CH₂)_(n)—(CHC₂H₅)_(m)—(CH₂)_(o)—CH₃ and species and groups describedbelow for alkenyl, alkynyl groups aryl groups, arylalkyl groupsalkylaryl groups and the like, where n, m and o independently are 0, 1,2, 3, 4, 5, 6, 7 or 8.

For any group or moiety described by a given range of carbon atoms, thedesignated range means that any individual number of carbon atoms isdescribed. Thus, reference to, e.g., “C1-C4 optionally substitutedalkyl”, “C₂₋₆ alkenyl”, or “C2-C6 optionally substituted alkenyl”,specifically means that a 1, 2, 3 or 4 carbon optionally substitutedalkyl moiety as defined herein is present, or a 2, 3, 4, 5 or 6 carbonalkenyl or optionally substituted alkenyl moiety as defined herein ispresent. All such designations are expressly intended to disclose all ofthe individual carbon atom groups and thus “C1-C4 optionally substitutedalkyl” means, e.g., 3 carbon alkyl, 4 carbon substituted alkyl and thelike are disclosed and can be expressly referred to or named.

“Alkenyl” as used here means a moiety that comprises linked normal,secondary, tertiary or cyclic carbon atoms, i.e., linear, branched,cyclic or any combination thereof, that comprises one or more doublebonds (e.g., —CH═CH—), e.g., 1, 2, 3, 4, 5, 6 or more, typically 1 or 2.The number of carbon atoms in an alkenyl group or moiety can vary andtypically is 2 to about 50, e.g., about 2-30 or about 2-20, unlessotherwise specified, e.g., C₂₋₈ alkenyl or C2-8 alkenyl means an alkenylmoiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms. When an alkenylgroup is specified, species may include methylene (═CH₂),methylmethylene (═CH—CH₃), ethylmethylene (═CH—CH₂—CH₃),═CH—CH₂—CH₂—CH₃, vinyl (—CH═CH₂), allyl,—(CH₂)_(n)—(CH═CH)—(CH₂)_(m)—CH₃, —(CH₂)_(n)—(CCH₃═CH)—(CH₂)_(m)—CH₃,—(CH₂)_(n)—(CH═CCH₃)—(CH₂)_(m)—CH₃ and—(CH₂)_(n)—(CH═CH)₀₋₁—(CH₂)_(m)—CH₂CH═CH₂, where n and m independentlyare 0, 1, 2, 3, 4, 5, 6, 7 or 8.

“Alkynyl” as used here means a moiety that comprises linked normal,secondary, tertiary or cyclic carbon atoms, i.e., linear, branched,cyclic or any combination thereof, that comprises one or more triplebonds (—C≡C—), e.g., 1, 2, 3, 4, 5, 6 or more, typically 1 or 2 triplebonds, optionally comprising 1, 2, 3, 4, 5, 6 or more double bonds, withthe remaining bonds being single bonds. The number of carbon atoms in analkenyl group or moiety can vary and typically is 2 to about 50, e.g.,about 2-30 or about 2-20, unless otherwise specified, e.g., C₂₋₈ alkynylor C2-8 alkynyl means an alkynyl moiety containing 2, 3, 4, 5, 6, 7 or 8carbon atoms. When an alkynyl group is specified, groups and species mayinclude —CCH, —CCCH₃, —CCCH₂CH₃, —CCC₃H₇, —CCCH₂C₃H₇,—(CH₂)_(n)—(C≡C)—(CH₂)_(m)—CH₃, and—(CH₂)_(n)—(C≡C)₀₋₁—(CH₂)_(m)—CH₂C≡CH, where n and m independently are0, 1, 2, 3, 4, 5, 6, 7 or 8.

“Aryl” means an aromatic ring or fused ring system with no ringheteroatoms, e.g., phenyl or naphthyl.

“Arylalkyl” means a moiety where an alkyl group is bonded to an arylgroup, i.e., -alkyl-aryl, where alkyl and aryl groups are as describedabove, e.g., —CH₂—C₆H₅ or —CH₂CH(CH₃)—C₆H₅.

“Alkylaryl” means a moiety where an aryl group is bonded to an alkylgroup, i.e., -aryl-alkyl, where aryl and alkyl groups are as describedabove, e.g., —C₆H₄—CH₃ or —C₆H₄—CH₂CH(CH₃).

“Substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”,substituted alkylaryl”, “substituted arylalkyl”, “substitutedheterocycle”, “substituted aryl”, “substituted monosaccharide” and thelike mean an alkyl, alkenyl, alkynyl, alkylaryl, arylalkyl heterocycle,aryl, monosaccharide or other group or moiety as defined or disclosedherein that has a substituent(s) that replaces a hydrogen atom(s) or asubstituent(s) that interrupts a carbon atom chain. Substitutedheterocycles may thus have a substituent bonded to a ring carbon or aring heteroatom such as a nitrogen. Substituents for any of thesemoieties include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more independentlyselected —O—, —S—, —NH—, —C(O)—, —C(O)OH, —C(O)OR^(15A), C(O)OR^(PR),C(O)SR^(15A), C(O)SR^(PR), CHO, —CHS, —CH₂SH, —C═N—, —OH, ═O, —OR^(15A),—OR^(PR), —C(O)OR^(PR), —O—C(O)H, —C(O)CH₃, —C(S)CH₃, —C(S)SH,C(S)SR^(15A), C(S)SR^(PR), C(O)CH₂OH, —C(O)CH₂F, —C(O)CH₂Cl, —C(O)CH₂Br,—C(O)CH₂I, —C(O)CF₂H, —C(O)CF₃, —C(O)NHCH₃, —C(O)NHC₂H₅, —C(O)NHC(CH₃)₃,—O—CH₂—C(O)—C(CH₃)₃, —C(O)—C(CH₃)₃, —O—CH(CH₃)—O—C(CH₃)₃, —C(O)O—,C(S)OR^(PR), —C(S)O—, —OC(O)—, —C(O)H, —OCH₂—, —CH₂—O—CH₂—,—(CH₂)₁₋₂—O—(CH₂)₂, —OCH₂CH₂—, —OCH₂O—, —OCH₂CH₂O—, —CH₂OH, —CH₂F,—CHF₂, —CF₃, —CH₂Cl, —CH₂Br, —CH₂I, —C₂H₄Cl, —C₂H₄Br, —C₂H₄I, —CH₂CH₂F,—CH₂CHF₂, —CH₂CF₃, —NH₂, —NHR^(15A), —N(R^(15A))₂, —N(R^(PR))₂,—NHR^(PR), —NHC(O)—, —CH₂—NR^(PR), —CH₂—NHR^(PR), —CH₂—NHC(O)—,—C(O)NH—, —C(O)NHR^(PR), —OC(O)NR^(PR), —OC(O)NHR^(PR), —C(═NH)—NH₂,—C(═NH)OH, —C(═N—NH₂)OH, —C(O)NHOH, ═NOH, ═NOCH₃, ═NOC₂H₅, ═NOC₃H₇,═NOC₄H₉, —NHR^(15A), ═NR^(15A), ═N—, —NR^(PR)C(O)NR^(PR)—,—NR^(PR)C(O)NHR^(PR), —NR^(PR)CH₂—, —NR^(PR)CH₂CH₂—, —NO₂, —ONO₂, —S—,—SH, —SR^(15A), —SR^(PR), ═S, —S(O)R^(15A), —S(O)OR^(15A), —S(O)—,—S(O)(O)—, —O—S(O)(O)—NR^(PR)—, —O—S(O)(O)—NR^(PR)—CH₂—, —CH₂—S(O)(O)H,—CH₂—NH—S(O)(O)H, —CHR^(15A), —NH—S(O)(O)H, —O—S(O)(O)—CHR^(15A)—, —CH,R^(15A)—O—S(O)(O)—, —CHR^(15A)—S(O)(O)—CHR^(15A)—, —S(O)(O)H,—CHR^(15A)—S(O)(O)H, —NH—S(O)(O)—NH—, —CHR^(15A)—NH—S(O)(O)—NH—,—CHR^(15A)—NH—S(O)(O)—NH—CHR^(15A), —NH—S(O)(O)—NHR^(PR),—NH—S(O)(O)—NH₂, —NH—S(O)(O)—NHCH₃, —NH—S(O)—NH—,—CHR^(15A)—NH—S(O)—NH—, —CHR^(15A)—NH—S(O)—NH—CHR^(15A),—NH—S(O)—NHR^(PR), —NH—S(O)—NH₂, —NH—S(O)—NHCH₃, —NH—S(O)—,—CHR^(15A)—NH—S(O)—, —NH—S(O)—CHR^(15A), —S(O)—NHR^(PR), —S(O)—NH₂,—S(O)—NHCH₃, —S(O)(O)—O—, —S(O)OR^(PR), —S(O)(O)OH, —OSO₃H₂,—S(O)(O)OR^(15A), —S(O)(O)OR^(PR), —S(O)OH, —S(O)OR^(15A), —S(O)OR^(PR),—S(O)R^(15A), —S(O)R^(PR), —CN, —SCN, —C(O)OH, —C(O)OR^(15A),—C(O)OR^(PR), —C(O)SH, —C(O)SR^(15A), —C(O)SR^(PR), —C(S)OH,—C(S)OR^(15A), —C(S)OR^(PR), —O—P(O)(O)OH, —O—P(O)(O)OR^(15A),—O—P(O)(O)OR^(15A), —O—P(S)(O)OH, —O—P(S)(O)OR^(15A), —O—P(S)(O)OR^(PR),—O—P(O)(O)SH, —O—P(O)(O)SR^(15A), —P(O)(O)SR^(PR), —F, —Cl, —Br, —I,—C═NH, —C═NCH₃, —C═NC₂H₅, —C(═S)—, —C₆H₅, —CH₂C₆H₅, —O-A8, —S-A8,—C(O)-A8, —OC(O)-A8, —C(O)O-A8, —OPO₃(R^(PR))₂, -amino acid-,—O-monosaccharide, —O-disaccharide, —S-monosaccharide, —S-disaccharide,a polymer, e.g., a PEG, and combinations of these moieties and salts onany of these moieties that can form a salt, where each R^(PR)independently is —H, an independently selected protecting group or bothR^(PR) together are a protecting group, A8 is C1-C10 optionallysubstituted alkyl, and R^(15A) independently are —H, —CH₃, —C₂H₅, —C₃H₇,—C₄H₉, —C(CH₃)₃, —CH₂OH, —C₂H₄OH, —C₃H₆OH, —C₄H₈OH —C(CH₂OH)(CH₃)₂,—C₃H₅, —C₄H₇, optionally substituted C1-10 alkyl, C1-10 perfluoroalkyl,optionally substituted aryl, optionally substituted C1-12 alkylaryl,optionally substituted C1-12 arylalkyl, optionally substituted allyl,optionally substituted heterocycle, optionally substituted C1-4alkyl-optionally substituted heterocycle or optionally substitutedheterocycle-optionally substituted C1-4 alkyl. Substituents areindependently chosen when more than one is present. Alkenyl and alkynylgroups that comprise a substituent(s), are optionally substituted at acarbon that is one or more methylene moiety removed from the doublebond, e.g., the substituent is optionally separated by one, two, threeor more independently selected —CH₂—, —CH(C₁₋₆ optionally substitutedalkyl)-, —CH(C₁₋₆ optionally substituted alkenyl)-, —CH(C₁₋₆ optionallysubstituted alkynyl)-, —CH(optionally substituted heterocycle)-,—CH(optionally substituted aryl-optionally substituted alkyl)- or—CH(optionally substituted alkyl-optionally substituted aryl)- moieties.Other substituted alkenyl and alkynyl moieties include ═CHOH,═CH-halogen, ═CH—COOR^(PR), ═CH—(CH₂)_(m)—NH₂, ═CH—(CH₂)_(m)—NH(C1-C6alkyl), ═CH—N(C1-C6 alkyl)₂, ═CH—CH₂OH, ═CH—CH₂-halogen,═CH—CH₂—COOR^(PR), ═CH—CH₂—NH₂, ═CH—CH₂—NH(C1-C6 alkyl), ═CH—CH₂—N(C1-C6alkyl)₂, ═CH—CH₂—CH₂OH, ═CH—CH₂—CH₂-halogen, ═CH—CHOH—CH₃,═CH—CHOH—CH₂—CH₃, ═CH—CH₂—CH₂—COOR^(PR), ═CH—CH₂—CH₂—NH₂,═CH—CH₂—CH₂—N(C1-C4 alkyl)₂, —CH═CH—(CH₂)_(m)—OH, —CH═CH-halogen,—CH═CH—CH₂OH, —CH═CH—CH₂-halogen, —C≡C-halogen, —C≡C—CH₂—NH₂,—C≡C—CH₂—NH(C1-C6 alkyl), —C≡C—CH₂—N(C1-C6 alkyl)₂, —C≡C—OH,—C≡C—COOR^(PR), —C≡C—CH₂-halogen, —C≡C—CH₂—OH and —C≡C—CH₂—COOR^(PR),where each alkyl moiety is the same or different, e.g., both are methyl,ethyl or propyl or one is methyl and the other is ethyl, propyl or butyland m is 1, 2, 3 or 4. The organic moieties and substitutions describedhere, and for other any other moieties described herein, usually willexclude obviously unstable moieties, e.g., —O—O—, except where suchunstable moieties are transient species that one can use to make acompound such as a F1C with sufficient chemical stability for the one ormore of the uses described herein.

“Heterocycle” or “heterocyclic” includes by way of example and notlimitation the heterocycles described in Paquette, Leo A.; “Principlesof Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968),particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry ofHeterocyclic Compounds, A series of Monographs” (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;and J. Am. Chem. Soc. 1960, 82:5566. Heterocycles are typically bondedto the steroid nucleus through a carbon, nitrogen or sulfur atom in theheterocycle ring.

Examples of heterocycles include by way of example and not limitationpyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidizedtetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl,indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl,6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl,pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl,2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl,indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,and isatinoyl.

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Typically, nitrogen bonded heterocyclesinclude 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl,and 1-piperidinyl.

“Heteroaryl” means an aromatic ring or two or more fused rings thatcontain one or more aromatic rings where the ring or fused ringscomprise 1, 2, 3 or more heteroatoms, usually oxygen (—O—), nitrogen(—NX—) or sulfur (—S—) where X is —H, a protecting group or C₁₋₆optionally substituted alkyl, usually —H. Examples are as described forheterocycle.

“Alcohol” as used herein means an alcohol that comprises a C₁₋₁₂ alkylmoiety substituted at a hydrogen atom with one hydroxyl group. Alcoholsinclude methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol,s-butanol, t-butanol, n-pentanol, i-pentanol, n-hexanol, cyclohexanol,n-heptanol, n-octanol, n-nonanol and n-decanol. The carbon atoms inalcohols can be straight, branched or cyclic. Alcohol includes anysubset of the foregoing, e.g., C₁₋₄ alcohols (alcohols having 1, 2, 3 or4 carbon atoms).

“Halogen” means fluorine, chlorine, bromine or iodine.

“Protecting group” means a moiety that prevents or reduces the atom orfunctional group to which it is linked from participating in unwantedreactions. For example, for —OR^(PR), R^(PR) may be hydrogen or aprotecting group for the oxygen atom found in a hydroxyl, while for—C(O)—OR^(PR), R^(PR) may be hydrogen or a carboxyl protecting group,for —SR^(PR), R^(PR) may be hydrogen or a protecting group for sulfur inthiols for instance, and for —NHR^(PR) or —N(R^(PR))₂—, R^(PR) may behydrogen or a nitrogen atom protecting group for primary or secondaryamines. Hydroxyl, amine, ketones and other reactive groups are found inF1Cs at, e.g., R¹ or R². These groups may require protection againstreactions taking place elsewhere in the molecule. The protecting groupsfor oxygen, sulfur or nitrogen atoms are usually used to preventunwanted reactions with electrophilic compounds, such as acylatingagents used, e.g., in steroid chemistry.

“Ester” means a moiety that contains a —C(O)—O— structure. Typically,esters as used here comprise an organic moiety containing about 1-50carbon atoms (e.g., about 2-20 carbon atoms) and 0 to about 10independently selected heteroatoms (e.g., O, S, N, P, Si), where theorganic moiety is bonded to a formula 1 steroid nucleus at, e.g., R¹ orR² through the —C(O)—O— structure, e.g., organic moiety-C(O)—O-steroidor organic moiety-O—C(O)-steroid. The organic moiety usually comprisesone or more of any of the organic groups described herein, e.g., C₁₋₂₀alkyl moieties, C₂₋₂₀ alkenyl moieties, C₂₋₂₀ alkynyl moieties, arylmoieties, C₂₋₉ heterocycles or substituted derivatives of any of these,e.g., comprising 1, 2, 3, 4 or more substituents, where each substituentis independently chosen. Exemplary substitutions for hydrogen or carbonatoms in these organic groups are as described above for substitutedalkyl and other substituted moieties. Substitutions are independentlychosen. The organic moiety includes compounds defined by the R₄variable. The organic moieties exclude obviously unstable moieties,e.g., —O—O—, except where such unstable moieties are transient speciesthat one can use to make a compound with sufficient chemical stabilityfor one or more of the uses described herein, including for synthesis ofthe formula 1 or other compounds. The substitutions listed above aretypically substituents that one can use to replace one or more carbonatoms, e.g., —O— or —C(O)—, or one or more hydrogen atom, e.g., halogen,—NH₂ or —OH. Exemplary esters include one or more independently selectedacetate, enanthate, propionate, isopropionate, isobutyrate, butyrate,valerate, caproate, isocaproate, hexanoate, heptanoate, octanoate,nonanoate, decanoate, undecanoate, phenylacetate or benzoate, which aretypically hydroxyl esters.

“Thioester” means a moiety that comprises a —C(O)—S— structure.Typically, thioesters as used here comprise an organic moiety containingabout 1-50 carbon atoms (e.g., about 1-20 carbon atoms) and 0 to about10 independently selected heteroatoms (e.g., O, S, N, P, Si), where theorganic moiety is bonded to a formula 1 steroid nucleus at a variablegroup such as R¹, R², R³, R⁴ or R¹⁰ through the —C(O)—S— structure,e.g., organic moiety-C(O)—S-steroid or organic moiety-S—C(O)-steroid.The organic moiety is as described above for esters.

“Thionoester” means a moiety that comprises a —C(S)—O— structure.Typically, thionoesters as used here comprise an organic moietycontaining about 1-50 carbon atoms (e.g., about 1-20 carbon atoms) and 0to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si),where the organic moiety is bonded to a formula 1 steroid nucleus at avariable group such as R¹, R², R³, R⁴ or R¹⁰ through the—C(S)—O—structure, e.g., organic moiety-C(S)—O-steroid or organicmoiety-O—C(S)-steroid. The organic moiety is as described above foresters.

“Acetal”, “thioacetal”, “ketal”, “thioketal” “spiro ring” and the likemean a cyclic organic moiety that is bonded to a steroid ring atom inthe F1Cs, e.g., steroid nucleus atoms at one, two or more of the 1, 2,3, 4, 6, 7, 11, 12, 15, 16, 17, 18 or 19 positions. Typically, acetalscomprise an organic moiety containing about 1-20 carbon atoms (e.g.,about 1-10 carbon atoms) and 0 to about 10 independently selectedheteroatoms (e.g., O, S, N, P, Si). For acetals (or ketals), the steroidnucleus atoms are usually carbons and the acetal is bonded to a steroidcarbon through two oxygen atoms. Thioacetals (or thioketals) are bondedto the steroid nucleus through one oxygen and one sulfur atom or, moreoften, through two sulfur atoms. One, two or more of e.g., R¹, R², R³,R⁴, R¹⁰ at the 2, 11 or 15 positions, R^(10A), R^(10B), R^(10C) andR^(10D), may be an independently selected acetal, thioacetal or spiroring in any of the F1Cs disclosed herein. The oxygen or sulfur atoms inketals and thioketals are linked by an optionally substituted alkylmoiety. Typically the alkyl moiety is an optionally substituted C1-C6alkylene or branched alkyl structure such as —C(CH₃)₂—, —CH(CH₃)—,—CH₂—, —CH₂—CH₂—, —C[(C2-C4 alkyl)₂]_(1, 2, 3)- or —[CH(C2-C4alkyl)]_(1, 2, 3)—. Acetals include moieties having the structure—O—[C(R³⁶)₂]₁₋₆—O—, —O—CH₂—[C(R³⁶)₂]₂—O—, —O—CH₂—CH₂—[C(R³⁶)₂]₂—O—,—O—CH₂—[C(R³⁶)₂]₂—CH₂—O—, and —O—CH₂—C(R³⁶)₂—O—, where each R³⁶independently is —H, —OH, ═O, ═S, —SH, —F, —Cl, —Br, —I or an organicmoiety such as C1-C6 alkyl (e.g., methyl, ethyl, hydroxymethyl orhalomethyl), C2-C6 alkenyl, C2-C6 alkenyl, aryl or an heterocycle, anyof which are optionally substituted, e.g., —CF₃ or —CH₂OH. In some ofthese embodiments, one R³⁶ is —H and the other is another atom ormoiety, e.g., —OH, methyl or a halogen. In other embodiments, neitherR³⁶ is —H, e.g., both are methyl. Thioacetals include moieties thatcomprise a —S—[C(R³⁶)₂]₁₋₆—O— or —S—[C(R³⁶)₂]₁₋₆—S— structure where theopen valences are bonded to the same carbon on the steroid nucleus.Typically, thioacetals as used here comprise an organic moietycontaining about 1-50 carbon atoms (e.g., about 2-20 carbon atoms) and 0to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si),where the organic moiety is bonded to a formula 1 steroid nucleus atvariable groups such as R¹, R², R³, R⁴ or R¹⁰ through the—S—[C(R³⁶)₂]_(m)—O— or —S—[C(R³⁶)₂]_(m)—S— structure, e.g.,17-steroid-S—[C(R³⁶)₂]_(m)—O-17-steroid,17-steroid-S—CH₂—CH₂—O-17-steroid,17-steroid-O—[C(R³⁶)₂]_(m)—S-17-steroid,17-steroid-S—[C(R³⁶)₂]_(m)—S-17-steroid,17-steroid-S—[C(R³⁶)₂]_(m)—O-17-steroid, where m is 1, 2, 3, 4, 5 or 6.The organic moiety is as described above for esters. Other exemplaryacetal and thioacetals are —O—C(CH₃)₂—O—, —O—CH₂—CH₂—CH₂—O—,—O—CH₂—CH₂—O—, —O—CH₂—O—, —O—C(CH₃)(heterocycle)-O—, —O—CH(heterocycle)-O—, —O—C(CH₃)(aryl)-O—, —O—CH (aryl)-O—, —S—C(CH₃)₂—O—,—S—C(CH₃)₂—S—, —S—CH₂—CH₂—O—, —S—CH₂—CH₂—S—, —S—CH₂—O—, —S—CH₂—S—,—O—C(CH₃)₂—CH₂—O—, —O—C(CH₃)₂—C(CH₃)₂—O—, —S—C(CH₃)₂—CH₂—O— and—O—C(CH₃)₂—CH₂—S—. Some of these moieties can serve as protecting groupsfor a ketone or hydroxyl, e.g., acetals such as —O—CH₂—CH₂—CH₂—O— or—O—CH₂—CH₂—O— for ketones, which form a spiro ring that can be removedby chemical synthesis methods or by metabolism in cells or biologicalfluids. For any spiro ring disclosed herein and unless otherwisespecified, the 1^(st) and 2^(nd) open valences can be bonded to thecarbon in the steroid nucleus in the α- and β-configurationsrespectively or in the α- and β-configurations respectively. Forexample, in a spiro —NH—CH₂—CH₂—O— structure, the 1^(st) open valence,i.e., at the nitrogen atom, can be, e.g., at the 17-position in theβ-configuration and the 2^(nd) open valence, i.e., at the oxygen, wouldthen be in the α-configuration.

“Phosphoester” or “phosphate ester” means a moiety that comprises a—O—P(OR^(PR))(O)—O— structure where R^(PR) is hydrogen (—H), aprotecting group or an organic moiety as described for esters.Typically, phosphoesters as used here comprise a hydrogen atom, aprotecting group or an organic moiety containing about 1-50 carbon atomsand 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P,Si) linked to a formula 1 steroid nucleus at a variable group such asR¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸ through the —O—P(O)(O)—O— structure, e.g.,organic moiety-O—P(O)(OH)—O-steroid. The organic moiety is as describedabove for esters. Exemplary phosphoesters include —O—P(O)(OH)—O—CH₃,—O—P(O)(OCH₃)—O—CH₃, —O—P(O)(OH)—O—CH₂—CH₃, —O—P(O)(OC₂H₅)—O—CH₂—CH₃,—O—P(O)(OH)—O—CH₂—CH₂—CH₃, —O—P(O)(OH)—O—CH(CH₃)—CH₃,—O—P(O)(OH)—O—CH₂—CH₂—CH₂—CH₃, —O—P(O)(O(CH₃)₃)—O—C(CH₃)₃ and—O—P(O)(OH)—O—C(CH₃)₃.

“Phosphothioester” means a moiety that comprises a —O—P(SR^(PR))(O)—O—structure where R^(PR) is —H, a protecting group or an organic moiety asdescribed for esters. Typically, phosphothioesters as used here comprisea hydrogen atom, a protecting group or an organic moiety containingabout 1-50 carbon atoms and 0 to about 10 independently selectedheteroatoms (e.g., O, S, N, P, Si) linked to a formula 1 steroid nucleusat a variable group such as R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸ through the—O—P(O)(O)—O— structure, e.g., organic moiety-O—P(O)(SH)—O-steroid. Theorganic moiety is as described above for esters. Exemplaryphosphothioesters are as described for phosphoesters, except that sulfurreplaces the appropriate oxygen atom.

“Phosphonoester” means a moiety that comprises a —P(OR^(PR))(O)—structure where R^(PR) is —H, a protecting group or an organic moiety asdescribed for esters. Typically, phosphonoesters as used here comprise ahydrogen atom, a protecting group or an organic moiety containing about1-50 carbon atoms and 0 to about 10 independently selected heteroatoms(e.g., O, S, N, P, Si) linked to a formula 1 steroid nucleus at avariable group such as R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸ through the—P(OR^(PR))(O)—O— structure, i.e., organicmoiety-P(OR^(PR))(O)—O-steroid or steroid-P(OR^(PR))(O)—O-organicmoiety. The organic moiety is as described above for esters.

“Phosphiniester” means a moiety that comprises a —P(O)H— structure whereR^(PR) is —H, a protecting group or an organic moiety as described foresters. Typically, phosphiniesters as used here comprise a hydrogenatom, a protecting group or an organic moiety containing about 1-50carbon atoms and 0 to about 10 independently selected heteroatoms (e.g.,O, S, N, P, Si) linked to a formula 1 steroid nucleus at a variablegroup such as R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸ through the —P(O)H— structure,i.e., organic moiety-P(O)H-steroid or steroid-P(O)H-organic moiety. Theorganic moiety is as described above for esters.

“Sulfate ester” means a moiety that comprises a —O—S(O)(O)—O— structure.Typically, sulfate esters as used here comprise a hydrogen atom, aprotecting group or an organic moiety containing about 1-50 carbon atomsand 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P,Si) linked to a formula 1 steroid nucleus at a variable group such asR¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸ through the —O—S(O)(O)—O— structure, e.g.,organic moiety-O—S(O)(O)—O-steroid. The organic moiety is as describedabove for esters.

“Sulfite ester” means a moiety that comprises a —O—S(O)—O— structure.Typically, sulfite esters as used here comprise an organic moietycontaining about 1-50 carbon atoms and 0 to about 10 independentlyselected heteroatoms (e.g., O, S, N, P, Si) linked to a formula 1steroid nucleus at a variable group such as R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸through the —O—S(O)—O— structure, e.g., organic moiety-O—S(O)—O-steroid.The organic moiety is as described above for esters.

“Sulfamate ester”, “sulfamate derivative”, “sulfamate” and the like meana moiety that comprises a —O—S(O)(O)—NH— or —O—S(O)(O)—NH₂ structure.Typically, sulfamate derivatives as used here comprise an organic moietycontaining about 1-50 carbon atoms and 0 to about 10 independentlyselected heteroatoms (e.g., O, S, N, P, Si) linked to a formula 1steroid nucleus at a variable group such as R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸through a suitable structure such as —O—S(O)(O)—NH—, e.g., organicmoiety-O—S(O)(O)—NH-steroid, steroid-O—S(O)(O)—NH-organic moiety orsteroid-O—S(O)(O)—NH₂. The organic moiety is as described above foresters.

“Sulfamide” and the like mean a moiety that comprises a —NH—S(O)(O)—NH—or —NH—S(O)(O)—NH₂ structure. Typically, sulfamide moieties comprise anorganic moiety containing about 1-50 carbon atoms and 0 to about 10independently selected heteroatoms (e.g., O, S, N, P, Si) linked to aformula 1 steroid nucleus at a variable group such as R¹-R⁶, R¹⁰, R¹⁵,R¹⁷ or R¹⁸ through a suitable structure such as —NH—S(O)(O)—NH—, e.g.,steroid-NH—S(O)(O)—NH-organic moiety, steroid-NH—S(O)(O)—NH₂,steroid-NH—S(O)(O)—NHR^(PR) or steroid-NH—S(O)(O)—N(R^(PR))₂, whereR^(PR) independently or together are a protecting group such as C1-C8optionally substituted alkyl. The organic moiety is as described abovefor esters.

“Sulfinamide” and the like mean a moiety that comprises a —C—S(O)—NH—structure. Typically, sulfinamide moieties comprise an organic moietycontaining about 1-50 carbon atoms and 0 to about 10 independentlyselected heteroatoms (e.g., O, S, N, P, Si) linked to a formula 1steroid nucleus at a variable group such as R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸through a suitable structure such as steroid-S(O)—NH-organic moiety,steroid-NH—S(O)-organic moiety, steroid-S(O)—NH₂, steroid-S(O)—NHR^(PR)moiety or steroid-S(O)—N(R^(PR))₂, where R^(PR) independently ortogether are a protecting group such as C1-C8 optionally substitutedalkyl. The organic moiety is as described above for esters.

“Sulfurous diamide” and the like mean a moiety that comprises a—NH—S(O)—NH— or —NH—S(O)—NH₂ structure. Typically, sulfurous diamidemoieties comprise an organic moiety containing about 1-50 carbon atomsand 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P,Si) linked to a formula 1 steroid nucleus at a variable group such asR¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸ through a suitable structure such as—C—NH—S(O)—NH—C— or —CH₂—NH—S(O)—NH—CH₂—, e.g.,steroid-NH—S(O)—NH-organic moiety, steroid-NH—S(O)—NH₂,steroid-NH—S(O)—NHR^(PR) or steroid-NH—S(O)—N(R^(PR))₂, where R^(PR)independently or together are a protecting group such as C1-C8optionally substituted alkyl. The organic moiety is as described abovefor esters.

“Sulfonate ester”, “sulfonate derivative”, “sulfonate” and the like meana moiety that comprises a —O—S(O)(O)— or —S(O)(O)—O— structure.Typically, sulfonate derivatives comprise an organic moiety containingabout 1-50 carbon atoms and 0 to about 10 independently selectedheteroatoms (e.g., O, S, N, P, Si) linked to a formula 1 steroid nucleusat a variable group such as R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸ through asuitable structure such as —S(O)(O)—O—, e.g., organicmoiety-O—S(O)(O)-steroid, HO—S(O)(O)-steroid or organicmoiety-S(O)(O)—O-steroid. The organic moiety is as described above foresters.

“Amide”, “amide derivative” and the like mean an organic moiety asdescribed for ester that comprises a —C(O)—NR^(PR)— or —C(O)—NH— moiety,where R^(PR) is —H or a protecting group. In some embodiments, the—C(O)NR^(PR)— group is linked to the steroid nucleus at a variable groupsuch as R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸, i.e., organicmoiety-C(O)NR^(PR)-steroid, organic moiety-C(O)—NH-steroid orsteroid-C(O)NR^(PR)-organic moiety. The organic moiety is as describedabove for esters.

“Ether” means an organic moiety as described for ester that comprises 1,2, 3, 4 or more —O— moieties, usually 1 or 2. In some embodiments, the—O— group is linked to the steroid nucleus at a variable group such asR¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸, e.g., organic moiety-O-steroid. The organicmoiety is as described above for esters.

“Thioether” means an organic moiety as described for ester thatcomprises 1, 2, 3, 4 or more —S— moieties, usually 1 or 2. In someembodiments, the —S— group is linked to the steroid nucleus at avariable group such as R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸, e.g., organicmoiety-S-steroid, organic moiety-S—CH₂—S-steroid or organicmoiety-S—S-steroid. The organic moiety is as described above for esters.

“Acyl group” or “acyl” means an organic moiety as described for esterthat comprises 1, 2, 3, 4 or more —C(O)— groups. In some embodiments,the —C(O)— group is linked to the steroid nucleus at a variable groupsuch as R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸, e.g., organic moiety-C(O)-steroid.The organic moiety is as described above for esters. Exemplary acylmoieties include moieties such as —C(O)—N(C1-C6 alkyl)₂, —C(O)—NH(C1-C6alkyl), —C(O)—NH—C(CH₃)₃, —C(O)—NH—CH(CH₃)₂, —C(O)—NH—C(CH₃)₂—CH₃,—C(O)—NH—CH(CH₃)—CH₃, —C(O)—NH—C(CH₃)—CH₂—CH₃, —C(O)NH₂, —C(O)NHR^(PR),—C(O)—CH₃, —C(O)—CH₂—CH₃, —C(O)—CH₂—CH₂—CH₃, —C(O)—CH₂OH,—C(O)—CH₂OR^(PR), —C(O)—CH₂—CH₂H, —C(O)—CH₂—CH₂OR^(PR),—C(O)—CH₂-halogen, —C(O)—CH₂—CH₂-halogen, —C(O)—CH₂—COOR^(PR),—C(O)—CH₂—CH₂—COOR^(PR), —C(O)—CH₂—CH₂—CHOH, —C(O)—CH₂—NH₂,—C(O)—CH₂—NHR^(PR), —C(O)—CH₂—N(R^(PR))₂, —C(O)—CH₂—NH—(C1-C6 alkyl),—C(O)—CH₂—N(C1-C6 alkyl)₂, —C(O)—NH—CH═CH₂, —C(O)—NH—C≡CH, —C(O)—NH—CH₃,—C(O)—NH—CN, —C(O)—NH—CH₂—CN, where each alkyl is the same or differentand is optionally independently substituted and each R^(PR) is —H or anindependently selected protecting group for the atom or functional groupto which it is attached, or two R^(PR) together are a protecting groupfor the atom or functional group to which they are attached.

“Thioacyl” means an organic moiety as described for ester that comprises1, 2, 3, 4 or more —C(S)— groups. In some embodiments, the —C(S)— groupis linked to the steroid nucleus at a variable group such as R¹-R⁶, R¹⁰,R¹⁵, R¹⁷ or R¹⁸, e.g., organic moiety-C(S)-steroid. The organic moietyis as described above for esters. Exemplary thioacyl moieties includemoieties as described above for the acyl group, except that sulfurreplaces the appropriate oxygen atom.

“Carbonate” means an organic moiety as described for ester thatcomprises 1, 2, 3, 4 or more —O—C(O)—O— structures. Typically, carbonategroups as used here comprise an organic moiety containing about 1-50carbon atoms and 0 to about 10 independently selected heteroatoms (e.g.,O, S, N, P, Si) linked to a formula 1 steroid nucleus at a variablegroup such as R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸ through the —O—C(O)—O—structure, e.g., organic moiety-O—C(O)—O-steroid. The organic moiety isas described above for esters.

“Carbamate” means an organic moiety as described for ester thatcomprises 1, 2, 3, 4 or more —O—C(O)NR^(PR)— structures where R^(PR) is—H, a protecting group or an organic moiety as described for ester.Typically, carbamate groups as used here comprise an organic moietycontaining about 1-50 carbon atoms and 0 to about 10 independentlyselected heteroatoms (e.g., O, S, N, P, Si) linked to a formula 1steroid nucleus at a variable group such as R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ or R¹⁸through the —O—C(O)—NR^(PR)— structure, e.g., organicmoiety-O—C(O)—NR^(PR)-steroid or steroid-O—C(O)—NR^(PR)-organic moiety.The organic moiety is as described above for esters.

As used herein, “monosaccharide” means a polyhydroxy aldehyde or ketonehaving the empirical formula (CH₂O)_(n) where n is 3, 4, 5, 6 or 7.Monosaccharide includes open chain and closed chain forms, but willusually be closed chain forms. Monosaccharide includes hexofuranose andpentofuranose sugars such as 2′-deoxyribose, ribose, arabinose, xylose,their 2′-deoxy and 3′-deoxy derivatives and their 2′,3′-dideoxyderivatives. Monosaccharide also includes the 2′,3′ dideoxydidehydroderivative of ribose. Monosaccharides include the D-, L- and DL-isomersof glucose, fructose, mannose, idose, galactose, allose, gulose,altrose, talose, fucose, erythrose, threose, lyxose, erythrulose,ribulose, xylulose, ribose, arabinose, xylose, psicose, sorbose,tagatose, glyceraldehyde, dihydroxyacetone and their monodeoxy or otherderivatives such as rhamnose and glucuronic acid or a salt of glucuronicacid. Monosaccharides are optionally protected or partially protected.Exemplary monosaccharides include

where R³⁷ independently is hydrogen, a protecting group, acetamido(—NH—Ac), optionally substituted alkyl such as methyl or ethyl, or anester such as acetate or proprionate, R³³ is hydrogen, hydroxyl, —NH₂,—NHR^(PR), optionally substituted alkyl such as methyl or ethyl, or acation such as NH₄ ⁺, Na⁺ or K⁺ and R³⁹ is hydrogen, hydroxyl, acetate,proprionate, optionally substituted alkyl such as methyl, ethyl, methoxyor ethoxy.

Optionally substituted alkyl group, optionally substituted alkenylgroup, optionally substituted alkynyl group, optionally substituted arylmoiety and optionally substituted heterocycle mean an alkyl, alkenyl,alkynyl, aryl or heterocycle moiety that contains an optionalsubstitution(s). Such moieties include C₁₋₂₀ alkyl moieties, C₂₋₂₀alkenyl moieties, C₂₋₂₀ alkynyl moieties, aryl moieties, C₂₋₉heterocycles or substituted derivatives of any of these.

Optionally substituted “monosaccharide” comprise any C3-C7 sugar, D-, L-or DL-configurations, e.g., erythrose, glycerol, ribose, deoxyribose,arabinose, glucose, mannose, galactose, fucose, mannose, glucosamine,N-acetylneuraminic acid, N-acetylglucosamine, N-acetylgalactosamine thatis optionally substituted at one or more hydroxyl groups or hydrogen orcarbon atoms. Suitable substitutions are as described above forsubstituted alkyl moieties and include independently selected hydrogen,hydroxyl, protected hydroxyl, carboxyl, azido, cyano, —O—C₁₋₆ alkyl,—S—C₁₋₆ alkyl, —O—C₂₋₆ alkenyl, —S—C₂₋₆ alkenyl, ester, e.g., acetate orproprionate, optionally protected amine, optionally protected carboxyl,halogen, thiol or protected thiol. The linkage between themonosaccharide and the steroid is α or β.

Optionally substituted “oligosaccharide” comprises two, three, four ormore of any C3-C7 sugars that are covalently linked to each other. Thelinked sugars may have D-, L- or DL-configurations. Suitable sugars andsubstitutions are as described for monosaccharides. The linkage betweenthe oligosaccharide and the steroid is α or β, as are the linkagesbetween the monosaccharides that comprise the oligosaccharide. Adjacentmonosaccharides may be linked by, e.g., 1→2, 1→3, 1→4, and/or 1→6glycosidic bonds.

Nucleoside includes 3TC, AZT, D4T, ddI, ddC, G, A, U, C, T, dG, dA, dTand dC.

Polymer includes biocompatible organic polymers, e.g.,polyethyleneglycols (“PEGs”) and polyhydroxyalkyl polymers. PEG means anethylene glycol polymer that contains about 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12 or more linked monomers, e.g., about 50-1000 linked monomers.Average molecular weights typically are about 80, 100, 200, 300, 400 or500, and mixtures thereof may are included, e.g., PEG100 and PEG200,PEG200 and PEG300, PEG100 and PEG300 or PEG200 and PEG400.

As used herein, position numbers that are given for the F1Cs use thenumbering convention for cholesterol.

Spiro ring substituents are cyclic structures that are usually 3, 4, 5,6, 7 or 8 membered rings, e.g., they include 3, 4-, 5-, 6-, 7- or8-sided rings. In some embodiments, spiro structures share a carbon atomthat is present in the steroid ring system, e.g., at the 2, 3, 7, 11,15, 16 or 17 positions of the F1Cs. Spiro structures include, acetals,thioacetals and lactone rings or cyclic esters. Spirolactones, spiroring compounds and dihydroxy F1Cs containing cyclic diol groups includeF1Cs having the structures

where X is —C(R¹⁰)₂— or —CHR¹⁰—, and R¹⁰ are independently selected. Insome of these embodiments, the R¹⁰, R^(10A), R^(10B), R^(10C) andR^(10D) variable groups are in the α- or β-configuration and areindependently selected from —H, —F, —Cl, —Br, —OH, —OCH₃, —OC₂H₅, anoptionally substituted ester such as acetate or propionate, anoptionally substituted alkyl such as methyl or ethyl or an amino acid.

As used herein, “innate immunity” refers to one or more componentstypically associated with nonspecific immune defense mechanisms in asubject. These components include the alternate complement pathway,e.g., Factor B, Factor D and properdin; NK cells, phagocytes (monocytes,macrophages), neutrophils, eosinophils, dendritic cells, fibrocytes;anti-microbial chemicals, e.g., one or more of defensins; physicalbarriers—skin, mucosal epithelium; or certain interleukins, chemokines,cytokines, lung or alveolar macrophage respiratory burst activity or alung surfactant protein such as surfactant protein A or surfactantprotein D. Innate immunity plays a role in resistance to intracellularparasite infections, e.g., white blood cell infection, a liverinfection, and other infections, e.g., lymph node infections. Detectableenhancement of innate immunity mechanism by F1Cs or method describedherein can also enhance phagolysosome fusion or movement, which somepathogens, e.g., intracellular bacteria such as mycobacteria, orListeria inhibit.

Terms such as “immune dysregulation”, “immune dysregulation condition”,“unwanted immune response” and the like mean that a subject has or issubject to developing an immune response that is not desirable or issuboptimal for the subject's condition. Such dysregulation or unwantedresponses can arise from various clinical conditions or diseases or as aresult of treatment of such conditions or diseases, e.g., inflammation,autoimmunity, organ or tissue transplant rejection (e.g., allograft,xenograft), infections, cancers, chemotherapy treatments, trauma,allergy conditions or in conditions where a subject mounts a Th1, Tc1,Th2 or Tc2 immune response that is considered to be pathogenic,ineffective, insufficient or suboptimal. Immune dysregulation conditionsare as described herein or in the cited references.

Terms such as “cellular response”, “cellular activity”, “biologicalresponse”, “biological activity” and the like mean a response oractivity that is detectably modulated in response to the presence of aF1C. Such responses or activities can be direct effects or indirecteffects on one or more cellular activities or on the expression or levelof one or more molecules that the affected cell(s) bind, sequester,synthesize or respond to. Such responses or activities include adetectable change in the synthesis or level of one or more cytokines,growth factors, transcription factors (including receptors and theircofactors), enzymes, Th1- or Th2-associated antibody subtype responsesor the like. Typically, the cytokines, growth factors, transcriptionfactors, enzymes or antibodies that are modulated are involved in theamelioration of a pathological condition or in the establishment,maintenance, severity or progression of a pathological condition.

As used herein, references to CD molecules, specific immune cellsubsets, immune responses and the like, generally use nomenclature thatapplies to molecules, cells or the like that are found in humans.Analogs or counterparts of such molecules, cells or the like in otherspecies may have a differing nomenclature, but are included in thisinvention. A description of the nomenclature and function of various CDmolecules and immune cell subsets are as found in the scientificliterature. References to Th0, Th1 or Th2 cells and references to Th1 orTh2 immune responses in the context of human patients refers to thehuman counterparts of the murine Th0, Th1 or Th2 immune cells orresponses. For reviews see, e.g., A. K. Abbas et al., editors, Cellularand Molecular Immunology, W.B. Saunders Company, third edition, 1997,ISBN 0-7216-4024-9, pages 4-469, and I. Kimber and M. K. Selgrade,editors, T Lymphocyte Subpopulations in Immunotoxicology, John Wiley &Sons Ltd., 1998, ISBN 0-471-97194-4, pages 1-53.

“Immunosuppressive molecule” means molecules such as cyclosporin,cyclohexamide, mitomycin C, adriamycin, taxol and amphotericin B. Thesemolecules tend to have toxicities toward the immune system and aredirectly or indirectly immunosuppressive, e.g., they are toxic todividing cells, they inhibit proliferation of immune cell precursors orthey can downregulate an otherwise desired or improved immune responseor condition.

“Nuclear hormone receptor” means a gene product, typically as a proteinmonomer or dimer that can bind to a ligand and affect transcription ofone or more genes. Ligands include, e.g., certain natural steroids,steroid analogs, F1Cs or another ligand such as a lipid, e.g., aprostaglandin, or the like. Nuclear hormone receptors include orphansteroid receptors, which typically function as heterodimers and theclassical steroid receptors, e.g., androgen receptor (“AR”), estrogenreceptor α (“ERα”), estrogen receptor β (“ERβ”), that function ashomodimers. Nuclear hormone receptors include species that formheterodimers, e.g., VDR-RXR or TR-RXR. Nuclear hormone receptors alsoinclude isoforms, e.g., PXR.1 and PXR.2 for the PXR receptor, Thenatural ligand and/or biological function for some orphan steroidreceptors is at least partially unknown. Nuclear hormone receptorsinclude the homologs of the receptors, e.g., the homolog of CARβ knownas MB67. Isoforms are typically generated by different splicing pathwaysfor a nuclear RNA from one gene, while homologs are typically a distinctcopy of a nuclear hormone receptor gene, where the gene copy encodesonly relatively small differences compared to the reference nuclearhormone receptor gene product. Such differences are most often found inareas other than the dimerization region and the steroid binding regionof the nuclear hormone receptor's structure. Typically isoforms andhomologs bind the same or similar ligands as the reference gene productor nuclear hormone receptor. Nuclear hormone receptors may be of humanor animal origin, e.g., obtained from cells, tissues or cDNA expressionlibraries derived from cells or tissues of any primate, rodent(including murine), avian, ovine, bovine, equine, canine, feline, insectspecies, e.g., Drosophila, nematode, e.g., Caenorhabditis elegans, orany of the species within any group (e.g., Family or Genus) of speciesmentioned herein or in any reference cited herein. Modulation of nuclearhormone receptors by F1Cs can arise from (1) their direct interactionwith the receptor or a cofactor thereof or (2) indirect effects such as(A) detectably increased or decreased synthesis or level of the receptoror (B) generation of a signal or stimulus that leads to detectablemodulation of one or more biological activities of the receptor, e.g.,detectable inhibition of receptor mediated gene transcription ordetectable enhancement of receptor mediated gene transcription.

An “agonist” or an “antagonist” is a compound or composition, usuallycontaining a F1C, that respectively, either detectably increases ordecreases the activity of a receptor, an enzyme or another biologicalmolecule, which can lead to increased or decreased transcription or mRNAlevels of a regulated gene or to another measurable effect such asaltered level of activity of the gene product or protein. The increaseor decrease in a receptor's or enzyme's activity will be an increase ora decrease of at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,90%, 95% or a range about between any two of these values, for one ormore measurable activities. Receptors, their accessory factors andassociated transcription factors can modulate transcription of theirtarget gene(s) by detectably increasing or decreasing transcription ormRNA levels. Biological activities of receptors may also includemodulating biological responses such as signal transduction within acell or ion flux, e.g., sodium, potassium or calcium, across cell ororganelle membranes, e.g., across mitochondria.

Terms such as “biologically active metabolite” and the like meanderivatives of the F1Cs that retain a detectable level, e.g., at leastabout 10%, at least about 20%, at least about 30% or at least about 50%,of at least one desired activity of the parent compound, e.g.,antiinflammatory activity or stimulation of a desired immune response.Determination of a desired activity is accomplished essentially asdescribed herein. Such metabolites can be generated in thegastrointestinal tract, in blood or in one or more subject tissues. Suchmetabolites are detected using standard analytical methods, e.g., GC-MSanalysis of an optionally radiolabeled F1C and its metabolites, inblood, urine or other biological samples after it is administered to asubject by one or more routes as disclosed herein. Terms such as“metabolic precursor” of F1Cs and the like can include compounds thatgenerate a detectable level of the F1C or a detectable level, e.g., atleast about 10%, at least about 20%, at least about 30% or at leastabout 50%, of at least one desired activity of the F1C. Determination ofa desired activity is accomplished essentially as described herein.Conversion of metabolic precursors can occur in the gastrointestinaltract, in blood or in one or more subject tissues.

“Amino acid” means an amino acid moiety that comprises anynaturally-occurring or synthetic amino acid residue, i.e., any moietycomprising at least one carboxyl and at least one amino residue directlylinked by one, two three or more carbon atoms, typically one (α) carbonatom. The nature and identity of the intervening structure locatedbetween the carboxyl and amino groups can have a variety of structuresincluding those described herein. Typically, amino acids linked to thesteroid through the amine group (“N-linked amino acid”) have sufficientconformation and length to be capable of autocatalytic hydrolysis of theamino acid-steroid bond and release of the steroid. This can occur whenthe free carboxyl is generated in vivo by deesterification, deamidationor peptidolytic cleavage of the precursor containing a linkage betweenthe amino acid's amine group and the steroid. Hydrolysis of the bondbetween an amino acid's carboxyl or amino group and the steroid can alsooccur by chemical or enzymatic activity, e.g., esterase cleavage ornon-enzymatic hydrolysis.

In general, the amino acids corresponding to the residues employed inthe F1Cs are naturally occurring and have no significant pharmacologicalactivity per se. However, optimal pharmacokinetic activity,(substantially complete hydrolysis upon hydrolysis of the distal amideor ester bond) may be achieved by using non-naturally occurring aminoacid residues. The intervening structure may be as simple as methylenewhen the amino acid residue is glycyl, or substituted methylene forother a amino acids. The structure ordinarily contains up to about 5carbon or heteroatoms in the direct linkage between the amino acid'scarboxyl carbon and the amine nitrogen. Thus, amino acids can compriseintervening ethylene, propylene, butylene, or pentylene groups or theirsubstituted analogs, such as for example, oxyesters or ethers in whichoxygen replaces carbon and, as appropriate, hydrogen. An example of suchan intervening structure would be —CH—O—C(R²²)(R²³)—, where R²² and R²³are independently selected hydrogen or organic moieties as describedabove for esters. In some embodiments one of R²² and R²³ is hydrogen andthe other is a C2-20 organic moiety. Typically the organic moietiescontain about 1-20 carbon atoms and 0, 1, 2, 3, 4 or 5 independentlyselected heteroatoms, which are typically selected from oxygen,nitrogen, sulfur and phosphorus. In general, fewer intervening atoms areused when more rapid hydrolysis is desired, although larger structuresare suitable if, e.g., they possess sufficient flexibility or haveconformations to allow positioning of the carboxyl group in proximity tothe amino acid-steroid bond.

Ordinarily, R²² is —H, methyl or hydroxymethyl, usually —H, and R²³ is aside chain or group of a naturally occurring amino acid. Amino acid sidechains include analogs where the side chain is a C₁₋₁₅ homolog of thecorresponding natural compound, e.g., methylene, ethylene, propylene,butylene or a substituted derivative thereof, e.g., an alkyl, ether oralkoxy (e.g., methoxy, ethoxy, propoxy) substituted derivative. Ingeneral, for carboxyl-containing side chains, if the C atom of the sidechain carboxyl is linked by 5 or less atoms to the N then the carboxyloptionally will be blocked, e.g. by esterification or amidation whereinthe ester or amide bonds are hydrolyzable in vivo. R²² also is takentogether with R³⁰ to form a proline residue (—CH₂—)₃. Thus, R²³ isgenerally a side group such as —H, —CH₃, —CH(CH₃)₂, —CH₂—CH(CH₃)₂,—CHCH₃—CH₂—CH₃, —CH₂—C₆H₅, —CH₂CH₂—S—CH₃, —CH₂OH, —CH(OH)—CH₃, —CH₂—SH,—CH₂—C₆H₄OH, —CH₂—CO—NH₂, —CH₂CH₂—CO—NH₂, —CH₂—COOH, —CH₂—CH₂—COOH,—(CH₂)₄—NH₂ and —(CH₂)₃—NH—C(NH₂)—NH₂. R²³ also includes1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl,indol-3-yl, methoxyphenyl and ethoxyphenyl. The optimal R³⁰ group isreadily selected using routine assays.

In general, the amino acid residue has the structure shown in theformulas below. Ordinarily, n is 1 or 2, R²² is —H and R²³ is a moietycontaining one or more of the following groups: amino, carboxyl, amide,carboxyl ester, hydroxyl, C₆-C₇ aryl, ether (—O—), thioether (—S—), n-,s- or t-alkyl (C₁-C₆), guanidinyl, imidazolyl, indolyl, sulfhydryl,sulfoxide, and phosphoryl. The R²² and R²³ substituents can have a widevariety of structures including those disclosed herein, e.g., esters,ethers or carbonates.

When the amino acid residues contain one or more chiral centers, any ofthe D, L, meso, threo or erythro (as appropriate) racemates or mixturesthereof, fall within the scope of this invention. In general, if it isdesired to rely on non-enzymatic means of hydrolysis, D isomers shouldbe used. On the other hand, L isomers may be more versatile since theycan be susceptible to both non-enzymatic as well as potential targetedenzymatic hydrolysis, and are more efficiently transported by amino acidor dipeptidyl transport systems in the gastrointestinal tract.

Examples of suitable amino acid residues include the following: Glycyl;aminopolycarboxylic acids, e.g., aspartic acid, β-hydroxyaspartic acid,glutamic acid, β-hydroxyglutamic acid, β-methylaspartic acid,β-methylglutamic acid, β,β-dimethylaspartic acid, γ-hydroxyglutamicacid, β,γ-dihydroxyglutamic acid, β-phenylglutamic acid,γ-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid,2-aminosuberic acid and 2-aminosebacic acid residues; amino acid amidessuch as glutaminyl and asparaginyl; polyamino- orpolybasic-monocarboxylic acids such as arginine, lysine, β-aminoalanine,γ-aminobutyrine, ornithine, citruline, homoarginine, homocitrulline,5-hydroxy-2,6-diaminohexanoic acid (commonly, hydroxylysine, includingallohydroxylysine) and diaminobutyric acid residues; other basic aminoacid residues such as histidinyl; diaminodicarboxylic acids such asα,α′-diaminosuccinic acid, α,α′-diaminoglutaric acid, α,α′-diaminoadipicacid, α,α′-diaminopimelic acid, α,α′-diamino-β-hydroxypimelic acid,α,α′-diaminosuberic acid, α,α′-diaminoazelaic acid, andα,α′-diaminosebacic acid residues; imino acids such as proline, 4- or3-hydroxy-2-pyrrolidinecarboxylic acid (commonly, hydroxyproline,including allohydroxyproline), γ-methylproline, pipecolic acid,5-hydroxypipecolic acid, —N([CH₂]_(n)COOR^(PR))₂, wherein n is 1, 2, 3,4, 5 or 6 and R^(PR) is —H or a protecting group, andazetidine-2-carboxylic acid residues; a mono- or di-alkyl (typicallyC₁-C₈ branched or normal) amino acid such as alanine, valine, leucine,allylglycine, butyrine, norvaline, norleucine, heptyline,α-methylserine, α-amino-α-methyl-γ-hydroxyvaleric acid,α-amino-α-methyl-δ-hydroxyvaleric acid,α-amino-α-methyl-ε-hydroxycaproic acid, isovaline, α-methylglutamicacid, α-aminoisobutyric acid, α-aminodiethylacetic acid,α-aminodiisopropylacetic acid, α-aminodi-n-propylacetic acid,α-aminodiisobutylacetic acid, α-aminodi-n-butylacetic acid,α-aminoethylisopropylacetic acid, α-amino-n-propylacetic acid,α-aminodiisoamyacetic acid, α-methylaspartic acid, α-methylglutamicacid, 1-aminocyclopropane-1-carboxylic acid; isoleucine, alloisoleucine,tert-leucine, β-methyltryptophan and α-amino-β-ethyl-β-phenylpropionicacid residues; β-phenylserinyl; aliphatic α-amino-β-hydroxy acids suchas serine, β-hydroxyleucine, β-hydroxynorleucine, β-hydroxynorvaline,and α-amino-β-hydroxystearic acid residues; α-Amino, α-, γ-, δ- orε-hydroxy acids such as homoserine, γ-hydroxynorvaline,δ-hydroxynorvaline and epsilon-hydroxynorleucine residues; canavinyl andcanalinyl; γ-hydroxyornithinyl; 2-Hexosaminic acids such asD-glucosaminic acid or D-galactosaminic acid residues; α-amino-β-thiolssuch as penicillamine, β-thiolnorvaline or β-thiolbutyrine residues;other sulfur containing amino acid residues including cysteine;homocystine; β-phenylmethionine; methionine; S-allyl-L-cysteinesulfoxide; 2-thiolhistidine; cystathionine; and thiol ethers of cysteineor homocysteine; phenylalanine, tryptophan and ring-substituted a aminoacids such as the phenyl- or cyclohexylamino acids α-aminophenylaceticacid, α-aminocyclohexylacetic acid and α-amino-β-cyclohexylpropionicacid; phenylalanine analogues and derivatives comprising aryl, loweralkyl, hydroxy, guanidino, oxyalkylether, nitro, sulfur orhalo-substituted phenyl (e.g., tyrosine, methyltyrosine and o-chloro-,p-chloro-, 3,4-dichloro, o-, m- or p-methyl-, 2,4,6-trimethyl-,2-ethoxy-5-nitro, 2-hydroxy-5-nitro and p-nitro-phenylalanine); furyl-,thienyl-, pyridyl-, pyrimidinyl-, purine or naphthylalanines; andtryptophan analogues and derivatives including kynurenine,3-hydroxykynurenine, 2-hydroxytryptophan and 4-carboxytryptophanresidues; α-amino substituted amino acid residues including sarcosine(N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine,N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline andN-benzylvaline; and α-Hydroxy and substituted α-hydroxy amino acidresidues including serine, threonine, allothreonine, phosphoserine andphosphothreonine residues.

Any one of the foregoing or other known amino acids are suitablyemployed in this invention. Typically, amino acids are capable ofautocatalytically hydrolyzing the amino acid-steroid bond. Thus, theytypically contain, or upon being hydrolyzed in vivo, contain a freecarboxyl group or amine group.

Also of interest are hydrophobic amino acids such as mono- or di-alkylor aryl amino acids, cycloalkylamino acids and the like. These residues,together with R²⁹-R³⁴ (R³¹-R³⁴ are defined below) can contribute to cellpermeability by modulating the lipophilicity of a F1C. Typically, theresidue does not contain a sulfhydryl or guanidino substituent.

Peptide means 2, 3 or more of the two or more amino acids as definedabove are bonded together, usually by an amide bond or normal peptidebond. Variable groups in the F1Cs such as R¹-R¹⁰ can comprise a peptide.Typically the amino acids are linked through normal peptide bonds, e.g.,—CO—NH—, between adjacent amino acid residues. Peptides comprisedipeptides (dimers), tripeptides (trimers), short peptides of 4, 5, 6,8, 10 or 15 residues, and longer peptides or proteins having about 100or more residues. F1Cs that comprise a peptide can be used asimmunogens, prodrugs or as synthetic precursors for other steroidderivatives. In one embodiment, the peptide will contain a peptidolyticenzyme cleavage site at the peptide bond linking the first residue andthe next residue distal to the steroid residue. Such cleavage sites areoptionally flanked by enzymatic recognition structures, e.g. particularresidues recognized by a hydrolytic enzyme, e.g., a peptidase located inthe serum or in cells.

Peptidolytic enzymes are well known, and in particular includecarboxypeptidases. Carboxypeptidases digest polypeptides by removingC-terminal residues, and are specific in many instances for particularC-terminal sequences. Such enzymes and their substrate requirements ingeneral are well known. For example, a dipeptide having a given pair ofresidues and a free carboxyl terminus is covalently bonded through itsα-amino group to the steroid nucleus. It is expected that the peptidewill be cleaved by the appropriate dipeptidase, protease or by chemicalhydrolysis, leaving the carboxyl of the proximal amino acid residue toautocatalytically cleave the amidate bond.

Examples of suitable dipeptidyl groups (designated by their singleletter symbols) are shown in the table below. The single letterdesignations are: Y tyrosine, G glycine, F phenylalanine, M methionine,A alanine, S serine, I isoleucine, L leucine, T threonine, V valine, Ppraline, L lysine, H histidine, Q glutamine, E glutamic acid, Wtryptophan, R arginine, D aspartic acid, N asparagine and C cysteine.

Dipeptides AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP,AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM,RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL,NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH,DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ,CG, CH, CI, CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC,EE, EQ, EG, EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN,QD, QC, QE, QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA,GR, GN, GD, GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY,GV, HA, HR, HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT,HW, HY, HV, IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP,IS, IT, IW, IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM,LF, LP, LS, LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL,KK, KM, KF, KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH,MI, ML, MK, MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ,FG, FH, FI, FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC,PE, PQ, PG, PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN,SD, SC, SE, SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA,TR, TN, TD, TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY,TV, WA, WR, WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT,WW, WY, WV, YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP,YS, YT, YW, YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM,VF, VP, VS, VT, VW, VY, VV

Such dipeptides include species where both amino acids are in the Lconfiguration, the D configuration or mixtures of configurations.

Tripeptides, i.e., 3 linked amino acid residues, are also usefulembodiments. Each amino acid in a tripeptide may be in an L, D or mixedconfiguration. Tripeptides include those where A, C, D, E, F, G, H, I,K, L, M, N, P, Q, R, S, T, V, W or Y is linked by a standard peptidebond to the amino or the carboxyl terminus of any of the dipeptideslisted above. The sequence —X1-pro-X2-(where X1 is any amino acid and X2is hydrogen, any amino acid residue or a carboxyl ester of proline) willbe cleaved by luminal carboxypeptidase to yield X1 with a free carboxyl,which in turn autocatalytically cleaves the amidate bond. X2 usuallywill be a benzyl ester of the carboxy group of X2. Other embodimentsinclude tetrapeptides such as ones where any two of the dipeptideslisted above, which may be the same or different dipeptides (e.g., AAand AA linked together or, e.g., AA and GI linked together), are linkedto each other by a peptide bond through the amino terminus or carboxylterminus. One, 2 or more tetrapeptides may bonded to the formula 1 orformula 2 compound through the tetrapeptide's amino or carboxylterminus.

In some embodiments, the formula 1 or formula 2 compound comprises oneor more amino acids or peptides having the structure (A), (B) or (C):(A)R³²—NH—{[C(R²⁹)(R³⁰)]_(b)—C(O)—N(R³¹)}_(f)—[C(R²⁹)(R³⁰)]_(a)—C(O)—O-steroid;(B)R³³—O—{C(O)—[C(R²⁹)(R³⁰)]_(d)—N(R³¹)}_(g)—C(O)—[C(R²⁹)(R³⁰)]_(c)—N(R³¹)—O-steroid;or(C)R³³—O—{C(O)—[C(R²⁹)(R³⁰)]_(d)—N(R³¹)}_(e)—C(O)—[C(R²⁹)(R³⁰)]_(c)—N(R³¹)—C(O)—O-steroid,wherein (A), (B) or (C) are independently selected and they are bondedto 1, 2, 3 or more of R¹ through R⁴, where each R²⁹-R³¹ is independentlyselected; R²⁹ independently are —H or a C1-C20 organic moiety (e.g.,C₁₋₆ alkyl, e.g. —CH₃ or —C₂H₅); R³⁰ independently are the side chain ofan amino acid, including the side chain of naturally occurring aminoacids as described above, e.g., —H, —CH₃, —CH₂C₆H₅; R³¹ is —H or aprotecting group; R³² and R³³ independently comprise —H, a protectinggroup, an ester or an amide where each atom or group is independentlychosen; a, b, c and d independently are 1, 2, 3, 4 or 5, usually 1; e, fand g independently are an integer from 0 to about 1000, typically theyindependently are 0, 1, 2, 3, 4, 5, 6, 7 or 8; a, b, c and dindependently are 1 or 2; e, f and g independently are 0, 1, 2, 3, 4 or5.

If the amino acid(s) or residue(s) has 2 or more amine groups, e.g., alysinyl or arginyl, or ornithinyl residue, then R²⁹ is usually —H andR³⁰ may comprise −[C(R³⁴)₂]_(n2)N(R^(PR))— where n2 is 0, 1, 2, 3, 4, 5or 6, R^(PR) is —H or a protecting group and each R³⁴ independently is—H, C₁-C₂₀ optionally substituted alkyl, C₆-C₂₀ optionally substitutedaryl, C₇-C₂₀ optionally substituted alkylaryl, C₇-C₂₀ optionallysubstituted arylalkyl, C₁-C₂₀ optionally substituted alkoxy, C₆-C₂₀optionally substituted aryloxy or hydroxyl. Such compounds will containa plurality of steroid moieties. For example when both the epsilon (ε)or delta (δ) and alpha (α) amino groups of lysine or ornithine aresubstituted with steroid moieties the amidate is believed to be capableof releasing two molecules of active drug, each expected to emerge underdifferent pharmacokinetics and therefore further sustaining the drugrelease.

Salts of F1Cs. Invention embodiments include salts and complexes ofF1Cs, including pharmaceutically acceptable or salts that are relativelynon-toxic. Some of the F1Cs have one or more moieties that carry atleast a partial positive or negative charge in aqueous solutions,typically at a pH of about 4-10, that can participate in forming a salt,a complex, a composition with partial salt and partial complexproperties or other noncovalent interactions, all of which we refer toas a “salt(s)”. Salts are usually biologically compatible orpharmaceutically acceptable or non-toxic, particularly for mammaliancells. Salts that are biologically toxic are optionally used withsynthetic intermediates of F1Cs. When a water-soluble composition isdesired, monovalent salts are usually used.

Metal salts typically are prepared by reacting the metal hydroxide witha compound of this invention. Examples of metal salts that areoptionally prepared in this way are salts containing Li⁺, Na⁺, and K⁺. Aless soluble metal salt can be precipitated from the solution of a moresoluble salt by adding a suitable metal compound. Invention salts may beformed from acid addition of certain organic acids, such as organiccarboxylic acids, and inorganic acids, such as alkylsulfonic acids orhydrogen halide acids, to acidic or basic centers on F1Cs, such as basiccenters on the invention pyrimidine base analogs. Metal salts includeones containing Na⁺, Li⁺, K⁺, Ca⁺⁺ or Mg⁺⁺. Other metal salts maycontain aluminum, barium, strontium, cadmium, bismuth, arsenic or zincion.

Salt(s) of F1Cs may comprise a combination of appropriate cations suchas alkali and alkaline earth metal ions or ammonium and quaternaryammonium ions with the acid anion moiety of the phosphoric acid orphosphonic acid group, which may be present in polymers or monomers.

Salts are produced by standard methods, including dissolving free basein an aqueous, aqueous-alcohol or aqueous-organic solution containingthe selected acid, optionally followed by evaporating the solution. Thefree base is reacted in an organic solution containing the acid, inwhich case the salt usually separates directly or one can concentratethe solution.

Suitable amine salts include amines having sufficient basicity to form astable salt, usually amines of low toxicity including trialkyl amines(tripropylamine, triethylamine, trimethylamine), procaine,dibenzylamine, N-benzyl-betaphenethylamine, ephenamine,N,N′-dibenzylethylenediamine, N-ethylpiperidine, benzylamine anddicyclohexylamine.

Salts include organic sulfonic acid or organic carboxylic acid salts,made for example by addition of the acids to basic centers, typicallyamines. Exemplary sulfonic acids include C₆₋₁₆ aryl sulfonic acids,C₆₋₁₆ heteroaryl sulfonic acids and C₁₋₁₆ alkyl sulfonic acids such asphenyl sulfonic acid, a-naphthalene sulfonic acid, β-naphthalenesulfonic acid, (S)-camphorsulfonic acid, methyl (CH₃SO₃H), ethyl(C₂H₅SO₃H), n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl,pentyl and hexyl sulfonic acids. Exemplary organic carboxylic and otheracids include C₁₋₁₆ alkyl, C₆₋₁₆ aryl carboxylic acids and C₄₋₁₆heteroaryl carboxylic acids such as acetic, glycolic, lactic, pyruvic,malonic, glutaric, tartaric, citric, fumaric, succinic, malic, maleic,oxalic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic,salicylic, nicotinic, 2-phenoxybenzoic, methanesulfonic, pamoic,propionic, toluenesulfonic and trifluoroacetic acids.

Invention salts include those made from inorganic acids, e.g., HF, HCl,HBr, HI, H₂SO₄, H₃PO₄, Na₂CO₃, K₂CO₃, CaCO₃, MgCO₃ and NaClO₃. Suitableanions, which are optionally present with a cation such a Ca⁺⁺, Mg⁺⁺,Li⁺, Na⁺ or K⁺, include arsenate, arsenite formate, sorbate, chlorate,perchlorate, periodate, dichromate, glycodeoxycholate, cholate,deoxycholate, desoxycholate, taurocholate, taurodeoxycholate,taurolithocholate, tetraborate, nitrate, nitrite, sulfite, sulfamate,hyposulfite, bisulfite, metabisulfite, thiosulfate, thiocyanate,silicate, metasilicate, CN⁻, gluconate, gulcuronate, hippurate, picrate,hydrosulfite, hexafluorophosphate, hypochlorite, hypochlorate, borate,metaborate, tungstate and urate.

Salts also include the F1C salts with one or more amino acids. Manyamino acids are suitable, especially the naturally-occurring amino acidsfound as protein components, although the amino acid typically is onebearing a side chain with a basic or acidic group, e.g., lysine,arginine, histidine or glutamic acid, or a neutral group such asglycine, serine, threonine, alanine, isoleucine, or leucine.

The invention compositions include F1Cs, their hydrates and thecompounds in their ionized, un-ionized, as well as zwitterionic form.Thus, for any F1Cs or compounds described herein with any substituentthat contains a moiety that is partially or completely ionizable, e.g.,a carboxyl group, the ionizable atom, usually hydrogen, may be replacedwith one or more suitable counter ions such as a monovalent metal, amultivalent metal, an alkaline metal, or an ionizable organic moiety,e.g., Li⁺, Na⁺, K⁺, Ca⁺², Mg⁺², SO₄ ⁻², PO₄ ⁻², CH₃C(O)O⁻, CF₃C(O)O⁻,F⁻, Cl⁻, Br⁻, I⁻, NH₄ ⁺, N⁺(CH₃)₄, N⁺(C₂H₅)₄, HN⁺(C₂H₅)₃, H₂N⁺(C₂H₅)₂,β-hydroxyethyltrimethylammonium, piperazinium, pyridinium,N-methylpyridinium, morpholimium, N,N-dimethylmorpholinium,p-toluidinium or another ionizable moiety described herein. When a F1Cis under conditions, e.g., in a solution, where such moieties canpartially or completely ionize, the ionizable moiety may be partially orcompletely charged, e.g., —C(O)—O⁻, —NH₃ ⁺, —C(O)—NH₃ ⁺ or —O—S(O)(O)—O⁻may be partially for fully ionized.

Stereoisomers. The F1Cs include enriched or resolved optical isomers atany or all asymmetric atoms as are apparent from the depictions or areincluded in the compound structures. Both racemic and diasteromericmixtures, as well as the individual optical isomers can be isolated orsynthesized so as to be substantially free of their enantiomeric ordiastereomeric partners, and these are all within the scope of theinvention. Chiral centers may be found in F1Cs at, for example, one ormore of R¹, R², R³, R⁴ or R¹⁰.

One or more of the following methods are used to prepare theenantiomerically enriched or pure isomers herein. The methods are listedin approximately their order of preference, i.e., one ordinarily shouldemploy stereospecific synthesis from chiral precursors beforechromatographic resolution before spontaneous crystallization.

Stereospecific synthesis is described in the examples. Methods of thistype conveniently are used when the appropriate chiral starting materialis available and reaction steps are chosen do not result in undesiredracemization at chiral sites. One advantage of stereospecific synthesisis that it does not produce undesired enantiomers that must be removedfrom the final product, thereby lowering overall synthetic yield. Ingeneral, those skilled in the art would understand what startingmaterials and reaction conditions should be used to obtain the desiredenantiomerically enriched or pure isomers by stereospecific synthesis.

If a suitable stereospecific synthesis cannot be empirically designed ordetermined with routine experimentation then those skilled in the artwould turn to other methods. One method of general utility ischromatographic resolution of enantiomers on chiral chromatographyresins. These resins are packed in columns, commonly called Pirklecolumns, and are commercially available. The columns contain a chiralstationary phase. The racemate is placed in solution and loaded onto thecolumn, and thereafter separated by HPLC. See for example, ProceedingsChromatographic Society—International Symposium on Chiral Separations,Sep. 3-4, 1987. Examples of chiral columns that could be used to screenfor the optimal separation technique would include Diacel Chriacel OD,Regis Pirkle Covalent D-phenylglycine, Regis Pirkle Type 1A, AstecCyclobond II, Astec Cyclobond III, Serva Chiral D-DL=Daltosil 100,Bakerbond DNBLeu, Sumipax OA-1000, Merck Cellulose Triacetate column,Astec Cyclobond I-Beta, or Regis Pirkle Covalent D-Naphthylalanine. Notall of these columns are likely to be effective with every racemicmixture. However, those skilled in the art understand that a certainamount of routine screening may be required to identify the mosteffective stationary phase. When using such columns it is desirable toemploy embodiments of the compounds of this invention in which thecharges are not neutralized, e.g., where acidic functionalities such ascarboxyl are not esterified or amidated.

Another method entails converting the enantiomers in the mixture todiasteriomers with chiral auxiliaries and then separating the conjugatesby ordinary column chromatography. This is a very suitable method,particularly when the embodiment contains free carboxyl, amino orhydroxyl that will form a salt or covalent bond to a chiral auxiliary.Chirally pure amino acids, organic acids or organosulfonic acids are allworthwhile exploring as chiral auxiliaries, all of which are well knownin the art. Salts with such auxiliaries can be formed, or they can becovalently (but reversibly) bonded to the functional group. For example,pure D or L amino acids can be used to amidate the carboxyl group ofinvention embodiments that comprise a carboxyl group and then separatedby chromatography.

Enzymatic resolution is another method of potential value. In suchmethods one prepares covalent derivatives of the enantiomers in theracemic mixture, generally lower alkyl esters (for example of carboxyl),and then exposes the derivative to enzymatic cleavage, generallyhydrolysis. For this method to be successful an enzyme must be chosenthat is capable of stereospecific cleavage, so it is frequentlynecessary to routinely screen several enzymes. If esters are to becleaved, then one selects a group of esterases, phosphatases, andlipases and determines their activity on the derivative. Typicalesterases are from liver, pancreas or other animal organs, and includeporcine liver esterase.

If the enantiomeric mixture separates from solution or a melt as aconglomerate, i.e., a mixture of enantiomerically pure crystals, thenthe crystals can be mechanically separated, thereby producing theenantiomerically enriched preparation. This method, however, is notpractical for large-scale preparations and is of limited value for trueracemic compounds. Asymmetric synthesis is another technique forachieving enantiomeric enrichment. For example, a chiral protectinggroup is reacted with the group to be protected and the reaction mixtureallowed to equilibrate. If the reaction is enantiomerically specificthen the product will be enriched in that enantiomer.

Embodiments of formula 1 compounds. For formula 1 compounds (“F1Cs”), 2,3 or more of R¹, R², R³ and R⁴ are usually not —H, and typically one orboth R¹ and R⁴, R³ and R⁴, R², R³ and R⁴ or R² and R⁴ are not —H, and/or1 or 2 of R^(10A), R^(10B), R^(10C) and R^(10D) are optionally not —H.For any F1C disclosed herein, steroid nucleus carbon atoms that containtwo variable groups (e.g., two R¹⁰ at R⁸ or R⁹ or two R³ or R⁴ at the16- or 17-position), each variable group is independently selected andeach can thus be the same or different, e.g., both can be methyl, ethyl,methoxy, ethoxy, —F, —Cl, —Br, —I, or they can be different. As isapparent from the F1C structures, a double bond can be present at eitherthe 4-5 position or at the 5-6 position, but not at both positions atthe same time. Steroid nucleus carbon atoms refers generally to thecarbons that make up the rings in F1Cs and carbons, if present, that arebonded to the 10, 13 and 17 positions. Additional carbons that may be atthe 17-position are typically numbered using the cholesterol numberingsystem, although any other suitable nomenclature can be used to describespecies or genera of F1C. Exemplary F1C embodiments are described below.

F1Cs include 16α-bromoepiandrosterone (“BrEA”) hemihydrate

which has previously been described, e.g., WO 00/56757. BrEA hemihydrateis used as a F1C either as a pure compound or substantially free ofother forms of BrEA, such as amorphous BrEA or anhydrous BrEA.

F1Cs include compounds having the structure 5, 6, 7, 8, 9 and 10,

or a metabolic precursor, a metabolite or salt thereof, wherein

each R¹, R², R³, R⁴, R¹⁰ at the 2, 11 and 15 positions, R^(10A),R^(10B), R^(10C) and R^(10D) independently are —H, —OH, —OR^(PR),—SR^(PR), —N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN, —NO₂, —ONO₂,—N₃, —NH₂, —COOH, —OSO₃H, —OPO₃H, ═O, ═S, ═NOH, ═CH₂, ═CH₂CH₃,═N—NH—C(═NH)—N(R^(PR))₂, ═N—NH—C(═NH)—NH₂, an ester, a thioester, athionoester, a phosphoester, a phosphothioester, a phosphonoester, aphosphiniester, a sulfite ester, a sulfate ester, a sulfoxide, asulfamate, a sulfonate, a sulfamide, a sulfinamide, a sulfurous diamide,an amide, an amino acid, a peptide, an ether, a thioether, an acylgroup, a thioacyl group, a carbonate, a carbamate, a halogen, an acetal,a thioacetal a spiro ring, an optionally substituted alkyl group, anoptionally substituted alkenyl group, an optionally substituted alkynylgroup, an optionally substituted aryl moiety, an optionally substitutedheteroaryl moiety, an optionally substituted heterocycle, an optionallysubstituted monosaccharide, an optionally substituted oligosaccharide, anucleoside, a nucleotide, an oligonucleotide, a polymer, or, one or moreof two adjacent R¹-R⁴, R¹⁰, R^(10A), R^(10B), R^(10C) and R^(10D) are anindependently selected epoxide or cyclopropyl ring;

R⁵, R⁶ and R¹⁰ at the 5 (if present), 8, 9 and 14 positionsindependently are —H, —CH₃, —C₂H₅, —OH, —OR^(PR), —SR^(PR), —N(R^(PR))₂,—O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN, —N₃, —COOH, —OS(O)(O)OH, an ester,a thioester, a thionoester, a sulfite ester, a sulfate ester, asulfoxide, a sulfamate, a sulfonate, a sulfamide, a sulfinamide, asulfurous diamide, an amide, an amino acid, a peptide, an ether, athioether, an acyl group, a thioacyl group, a carbonate, a carbamate, ahalogen, an optionally substituted alkyl group, an optionallysubstituted alkenyl group, an optionally substituted alkynyl group, anoptionally substituted aryl moiety, an optionally substituted heteroarylmoiety, an optionally substituted heterocycle, an optionally substitutedmonosaccharide, an optionally substituted oligosaccharide, or, one, twoor more of R⁵, R⁶ and R¹⁰ at the 5, 8, 9 and 14 positions, together witha carbon atom that is adjacent to the carbon to which the R⁵, R⁶ or R¹⁰at the 5, 8, 9 or 14 position is bonded are an independently selectedepoxide or cyclopropyl ring;

R⁷ is —C(R¹⁰)₂—, —C(R¹⁰)₂—C(R¹⁰)₂—, —C(R¹⁰)₂—C(R¹⁰)₂—C(R¹⁰)₂—,—C(R¹⁰)₂—O—C(R¹⁰)₂—, —C(R¹⁰)₂—S—C(R¹⁰)₂—, —C(R¹⁰)₂—NR^(PR)—C(R¹⁰)₂—,—O—, —O—C(R¹⁰)₂—, —S—, —S—C(R¹⁰)₂—, —NR^(PR), —NH— or —NR^(PR)—C(R¹⁰)₂—;

R⁸ and R⁹ independently are —C(R¹⁰)₂—, —C(R¹⁰)₂—C(R¹⁰)₂—, —O—,—O—C(R¹⁰)₂—, —S—, —S—C(R¹⁰)₂—, —NR^(PR)— or —NR^(PR)—C(R¹⁰)₂—, or one orboth of R⁸ or R⁹ independently are absent, leaving a 5-membered ring;

R¹³ independently is C₁₋₆ alkyl; and

R^(PR) independently are —H, a protecting group or together are aprotecting group, wherein 0, 1, 2, 3 or 4 of R^(10A), R^(10B), R^(10C)and R^(10D) are —H, R⁵ and R⁶ respectively are in the β,β, α,β, β,α orα,α configurations, and wherein, R¹⁰ moieties at the 5 (if present), 8,9 and 14 positions respectively are in the α,α,α,α, α,α,α,β, α,α,β,α,α,β,α,α, β,α,α,α, α,α,β,β, α,β,α,β, β,α,α,β, β,α,β,α, β,β,α,α, α,β,β,α,α,β,β,β, β,α,β,β, β,β,α,β, β,β,β,α or β,β,β,β configurations. For any ofthe F1Cs of structure 5, 6, 7, 8, 9 or 10 where two variable groups arebonded to the same carbon, e.g., R¹, R², R³, R⁴ or R¹⁰ at the 11position, the each variable group at that position is independentlyselected.

In the F1Cs, each R¹, R², R³, R⁴, R¹⁰ at the 2, 11 and 15 positions, isindependently selected. In some embodiments one of the R¹, R², R³, R⁴,R¹⁰ at the 2, 11 and 15 positions is hydrogen and the other is —Hanother moiety, but usually 2, 3, 4, 5 or 6 of the remaining variablegroups are not —H, i.e., they are another moiety as defined for thosegroups. In other embodiments, both R¹, R², R³, R⁴, R¹⁰ at the 2, 11 and15 positions, are independently selected moieties other than hydrogen,i.e., they are another moiety as defined for those groups such as aC1-C20 organic moiety or C1-C20 optionally substituted alkyl group. Inmany embodiments R¹ at the 1-position in the β-configuration or R¹ atthe 1-position in the α-configuration is not —H and R⁴ at the 1-positionin the β-configuration or R¹ at the 1-position in the α-configuration isnot —H.

F1Cs include compounds having structure 2

wherein, each R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ at the 2, 5, 8, 9,11, 14 and 15 positions, R^(10A), R^(10B), R^(10C) and R^(10D) are eachindependently chosen and have the meanings given above for compounds ofstructure 5, 6, 7, 8, 9 or 10;

R³ and R⁴ are, if present, both in the α-configuration or theβ-configuration or one of R³ and R⁴ is in the α-configuration and theother is in the β-configuration;

D is a heterocycle, a 4-, 5-, 6- or 7-membered carbon ring, or two fusedrings, each being 4-, 5-, 6- or 7-membered carbon ring, wherein 1, 2 or3 ring carbon atoms of the 4-, 5-, 6- or 7-membered carbon ring(s) areoptionally independently substituted with substituents described forsubstituted alkyl groups, e.g., —O—, —S— or —NR^(PR)— or where 1, 2 or 3hydrogen atoms of the heterocycle or where 1, 2 or 3 hydrogen atoms ofthe 4-, 5-, 6- or 7-membered ring are substituted with —OR^(PR),—SR^(PR), —N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS, —CN, —NO₂, —OSO₃H,—OPO₃H, ═O, ═S, ═N—OH, ═CH₂ or a spiro ring an ester, a thioester, athionoester, a phosphoester, a phosphothioester, a phosphonoester, aphosphiniester, a sulfite ester, a sulfate ester, a sulfoxide, asulfamate, a sulfonate, a sulfamide, a sulfinamide, a sulfurous diamide,an amide, an amino acid, a peptide, an ether, a thioether, an acylgroup, a thioacyl group, a carbonate, a carbamate, an acetal, athioacetal, a halogen, an optionally substituted alkyl group, anoptionally substituted alkenyl group, an optionally substituted alkynylgroup, an optionally substituted aryl moiety, an optionally substitutedheteroaryl moiety, an optionally substituted monosaccharide, anoptionally substituted oligosaccharide, a nucleoside, a nucleotide, anoligonucleotide or a polymer.

In some embodiments, D comprises two 5- or 6-membered rings, wherein therings are fused or are linked by 1 or 2 bonds, wherein 0, 1, 2 or 3 ofR⁷, R⁸ and R⁹ are not —CHR¹⁰— or —C(R¹⁰)₂—.

Exemplary F1C of structure 2 include the following structures,

wherein, R¹⁶ independently are —CH₂—, —O—, —S— or —NH—; R¹⁵, R¹⁷ and R¹⁸are independently selected R¹ moieties, e.g., —H, —OH, —OR^(PR), ═O,—SR^(PR), ═S, —O—Si—(R¹³)₃, ester, ether, acyl, halogen or an optionallysubstituted alkyl group; and R¹⁹ is nitrogen or CH; R¹-R¹⁰, R^(10A),R^(10B), R^(10C) and R^(10D) are each independently chosen and have themeanings given above for compounds of structure 5, 6, 7, 8, 9 or 10; R¹⁰moieties at the 5 (if present), 8, 9 and 14 positions respectively arein the α,α,α,α, α,α,α,β, α,α,β,α, α,β,α,α, β,α,α,α, α,α,β,β, α,β,α,β,β,α,α,β, β,α,β,α, β,β,α,α, α,β,β,α, α,β,β,β, β,α,β,β, β,β,α,β, β,β,β,αor β,β,β,β configurations; and R⁵ and R⁶ are in the β,β, β,α, α,β or α,αconfigurations. For F1Cs of structure 2 where two variable groups arebonded to the same carbon, e.g., R¹, R² or R¹⁰ at the 11 position, theeach variable group at that position is independently selected. As shownin the structure, the R¹⁷ moiety can be bonded to the ring carbonadjacent to R¹⁶, or it can be bonded to the adjacent 1, 2 or 3 ringcarbons. Similarly, the R¹⁸ moiety can be bonded to the ring carbonadjacent to R¹⁹, or it can be bonded to the adjacent 1, 2 or 3 ringcarbons. Structure 2 F1Cs can have 1, 2, 3 or 4 of R^(10A), R^(10B),R^(10C) and R^(10D) as —H, but usually 2 or 3 of R^(10A), R^(10B),R^(10C) and R^(10D) are —H, Structure 2 compounds include structureswherein one, two or three of R⁷, R⁸ and R⁹ are independently —O—, —S—,or —NH— or wherein one or both of R⁵ and R⁶ independently are —H, —CH₃,—CH₂OR^(PR), —CH₂OH, —CH₂SH, —CH₂SR^(PR), —CH₂O—C(O)—C₁₋₁₀ alkyl,—CH₂S—C(O)—C₁₋₁₀ alkyl, —CH₂O—C(O)—C₁₋₁₀ alkenyl, —CH₂S—C(O)—C₁₋₁₀alkenyl, —CH₂O—C(O)—C₀₋₄ alkyl-heterocycle, —CH₂S—C(O)—C₀₋₄alkyl-heterocycle, —CH₂O—C(O)—C₀₋₄ alkyl-phenyl, —CH₂S—C(O)—C₀₋₄alkyl-phenyl, wherein any C alkyl, heterocycle or phenyl moiety isoptionally substituted with one or more substituents, wherein the one ormore substituents are one, two, three or more independently selected—O—, ═O, or R^(PR), —S, ═S, —SR^(PR), —NH—, —N(R^(PR))₂ or —C(O)—NH—,wherein each R^(PR) independently is —H or a protecting group.

The structure 2 compounds described above include

where X independently are O or S, typically both X are O. R^(10α) is anindependently selected R¹⁰ moiety in the α-configuration, or if a doublebond is present, R^(10α) is absent, R^(10β) is an independently selectedR¹⁰ moiety in the β-configuration, R^(10F) is an independently selectedR¹⁰ moiety in the α- or β-configuration, n is 0, 1 or 2, and remainingvariable groups are as defined above. These compounds include ones whereR¹ in the α- and β-configurations independently are an R¹ moiety such asH, OH, halogen, an optionally substituted monosaccharide, an optionallysubstituted disaccharide or a dicarboxylic acid ester such as—OC(O)—(CH₂)₂—COOH, —OC(O)—(CH₂)₃—COOH or —OC(O)—(CH₂)₄—COOH, R² in theα- and β-configurations independently are an R² moiety such as —H, —OH,═O, —SH, ═S, halogen, optionally substituted alkyl, a monosaccharide ora disaccharide, R⁵ is C1-C4 alkyl, R⁶ is —H, halogen or C1-C4 alkyl orR⁷ and R⁸ independently are moieties as previously defined such asindependently selected —CH₂—, —CH(α-OR^(PR))—, —CH(β—OR^(PR))—, —C(O)—or —O—, R⁹ is a moiety as previously defined such as —CH₂—,—CH(α-halogen)-, —CH(α-OH)—, —CH(α-optionally substituted alkyl)-,—C(halogen)₂-, —C(β-optionally substituted alkyl)(α-OH)—,—CH(α-optionally substituted alkyl)-, R¹⁰ at the 9-position is a R¹⁰moiety such as —H, —F, —Cl, or optionally substituted alkyl, R^(PR) is—H or a protecting group such as an ester or optionally substitutedalkyl and other variable groups are as previously defined. For any ofthese compounds, 1, 2, 3 or 4 of R^(10A), R^(10B), R^(10C) and R^(10D)may be substituted, or they all be —H, while R¹⁷ may be a moiety definedpreviously such as C1-C6 optionally substituted alkyl, e.g., —CH₃ or—C₂H₅.

Monosaccharides and disaccharides are described above and are optionallybonded at one or more of R¹ or other variable groups in these structure2 or other formula 1 compounds include

where R^(10A) and RB independently are —H, —OH, halogen, —NH₂,—NHR^(PR), —N₃, C1-C6 alkoxy or -RD-RE, RC is —H, —OH, halogen, —NH₂,—NHR^(PR), —N₃, C1-C6 alkoxy or a monosaccharide or disaccharide linkedthrough a glycosidic bond, RD is —NH—C(O)—, —O—C(O)—,—O—C(O)—N(R^(PR))—, —NH—C(O)—N(R^(PR))—, —O—C(S)—N(R^(PR))— or—C(O)—N—(R^(PR))—, RE is aryl, arylalkyl, alkenyl, alkyl, cycloalkyl orcycloalkyl-alkyl, where each RE is optionally independently substitutedwith 1, 2 or 3 independently selected halogens, —OH, ═O, —SH, ═S, —NO₂,—CF₃, C1-C6 alkyl, phenoxy, C1-C6 alkoxy, methylenedioxy, C1-C6alkylsulfanyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, dimethylamino,mono- or di-C1-C6 alkylaminocarbonyl, C1-C6 alkylcarbonyl, C1-C6alkoxycarbonyl or pyrrolidinylcarbonyl, R^(PR) independently is —H or aprotecting group such as C1-C6 optionally substituted alkyl, ester suchas acetate or, if bonded to nitrogen, R^(PR) together with the nitrogento which it is attached is pyrrolidinyl, piperidinyl,N-methylpiperazinyl, indolinyl or morpholinyl, where the cyclic groupmay be monosubstituted on a carbon atom with C1-C6 alkoxycarbonyl orC1-C6 optionally substituted alkyl. In some of these embodiments, RA, RBand RC are —OH.

For any F1C of structure 2, 5, 6, 7, 8, 9 or 10, one, two or more ofR¹-R¹⁰, R^(10A), R^(10B), R^(10C), R^(10D), R¹⁵, R¹⁷ and R¹⁸ may bemoieties that are chemically and/or enzymatically hydrolysable orremovable, typically under physiological conditions, e.g., esters,thioesters, thionoesters, carbonates, amino acids, peptides and/orcarbamates. Such moieties are independently chosen. These moieties willtypically give rise to moieties such as to —OH, ═O, —SH or ═S at thesteroid nucleus. Embodiments of F1Cs include compounds where (1) one ofR¹, R² and R⁴ is a hydrolyzable moiety (e.g., ester, thioester,thionoester, carbonate, amino acid, peptide or carbamate), the other twoof R¹, R² and R⁴ are —H, R³ is not hydrogen and R⁵ and R⁶ are both —CH₃,(2) two of R¹, R² and R⁴ are hydrolyzable moieties (e.g., independentlychosen esters, thioesters, thionoesters, carbonates, amino acids,peptides and/or carbamates), the other of R¹, R² and R⁴ is —H, R³ is nothydrogen and R⁵ and R⁶ are both —CH₃, (3) R¹, R² and R⁴ are hydrolyzablemoieties, R³ is not hydrogen and R⁵ and R⁶ are both —CH₃. In theseembodiments, the R³ group is typically in the β-configuration and theR¹, R² and R⁴-R⁶ groups are typically in the α-configuration.

In other embodiments, one or more of R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ and R¹³,usually one, comprises an amino acid or a peptide, while the remaininggroups are independently selected from the moieties defined herein. Inthese embodiments, the peptides are typically dimers (dipeptides) ortrimers (tripeptides). For example one of R¹, R² or R⁴ comprises anamino acid, the remaining of R¹, R² or R⁴ independently comprise —OH,═O, an ester, a carbonate or a carbamate, while R³ is a halogen,hydroxyl or an ester and R⁵ and R⁶ independently are —H, —(CH₂)_(n)—CH₃,—(CH₂)_(n)—CH₂OH, or —(CH₂)_(n)—CH₂F, —(CH₂)₂₋₄—O—(CH₂)₂₋₄—CH₃, where nis 0, 1, 2, 3, 4, 5, 6, 7 or 8 often 0, 1, or 2, usually 0. Typicallythe ester, carbonate or carbamate are hydrolyzable under physiologicalconditions.

Hydrolyzable or removable moieties typically comprise acyl groups,esters, ethers, thioethers, amides, amino acids, peptides, carbonatesand/or carbamates. In general, the structure of hydrolyzable moieties isnot critical and can vary. In some embodiments, these moieties contain atotal of about 4 to about 10 carbon atoms. These hydrolyzable moietiesin other embodiments comprise an organic moiety, as described above forester, that contains 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 13, 14, 15 or 16carbon atoms and 1, 2, 3, 4, 5, 6, 7 or 8 heteroatoms, e.g., oxygen,nitrogen or sulfur. These hydrolyzable moieties can comprise no groupsthat are charged in plasma, blood, intracellular cytoplasm or in thegut, or they can comprise 1, 2, 3 or more positive, negative or positiveand negative charges under one or more of these conditions. The chargesmay be fractional depending on the group and the conditions it is under.These hydrolyzable moieties may comprise 1, 2, 3, 4 or moresubstitutions at a hydrogen atom(s) and/or a carbon atom(s), e.g., —OH,protected hydroxyl, —SH, protected thiol, carboxyl, protected carboxyl,amine, protected amine, —O—, —S—, —CO—, —CS—, alkoxy, alkylthio,alkenyloxy, aryl, —OP(O)(O)—O—, —OS(O)(O)—O— and/or heterocycle. Suchsubstitutions are independently selected. Embodiments of F1Cs includeones wherein one, two, three, four or more of the variable groups thatare bonded to the steroid rings, e.g., R¹-R⁶ or R¹⁰, comprise a moietythat can hydrolyze or metabolize to, e.g., a —H, —OH, ═O, —SH, ═S,—COOH, —NH₂, —CH₂OH, —CH₂SH, —C(O)—C1-C6 alkyl-OH, —C(O)—C1-C6 alkyl-SH,—C(S)—C1-C6 alkyl-OH, —C(O)—C1-C6 alkyl or —C(O)—NH₂ atom or group.

F1Cs that comprise a hydrolyzable or removable moiety(ies) may includeone or more independently chosen —O—CHR²⁴C(O)OR²⁵, —S—CHR²⁴C(O)OR²⁵,—NH—CHR²⁴C(O)OR²⁵, —O—CHR²⁴C(S)OR²⁵, —S—CHR²⁴C(S)OR²⁵,—NH—CHR²⁴C(S)OR²⁵, —O—CHR²⁴OC(O)R²⁵, —S—CHR²⁴OC(O)R²⁵,—NH—CHR²⁴OC(O)R²⁵, —O—CHR²⁴C(O)N(R²⁵)₂, —S—CHR²⁴C(O)N(R²⁵)₂,—NH—CHR²⁴C(O)N(R²⁵)₂, —O—CHR²⁴OR²⁵, —S—CHR²⁴OR²⁵, —NH—CHR²⁴OR²⁵,—O—CHR²⁴C(R²⁵)₂CH₂OX, —S—CHR²⁴C(R²⁵)₂CH₂OX, —NH—CHR²⁴C(R²⁵)₂CH₂OX,—O—CHR²⁴C(R²⁵)₂OX, —S—CHR²⁴C(R²⁵)₂OX or —NH—CHR²⁴C(R²⁵)₂OX, groups thatone or more of R¹-R⁶, R¹⁰, R¹⁵, R¹⁷ and R¹³ comprise. For thesehydrolyzable moieties, R²⁴ independently is —H, —CH₂—C₆H₅, —CH₂CH₂—C₆H₅,C₁₋₈ alkyl, C₂₋₈ alkenyl, aryl or heterocycle where each alkyl, alkenyl,aryl and heterocycle moiety is independently optionally substituted with1, 2, or 3, usually 1, —O—, —S—, —NH—, halogen, aryl, —OX, —SX, —NHX,ketone (═O) or —CN moieties or the C₁₋₈ alkyl is optionally substitutedwith 3, 4, 5 or 6 halogens, and X is —H or a protecting group. ExemplaryR²⁴ are —H, —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂—C₁₋₅ optionally substitutedalkyl, —CH₂CH₂—C₁₋₄ optionally substituted alkyl and —CH₂CH₂—O—C₁₋₄optionally substituted alkyl. R²⁵ independently is —H or a C₁₋₃₀ organicmoiety such as —CH₂—C₆H₅, —CH₂CH₂—C₆H₅, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl,C₂₋₁₂ alkynyl, aryl, a heterocycle, —CH₂-heterocycle or —CH₂-aryl, whereeach alkyl, alkenyl, alkynyl, aryl, heterocycle, —CH₂-heterocycle or—CH₂-aryl moiety is independently optionally substituted with 1 or 2,usually 1, —O—, —S—, —NH—, halogen, aryl, —OX, —SX, —NHX, ketone (═O),—C(O)OX or —CN moieties or the C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl or aryl, areoptionally independently substituted with 3, 4, 5 or 6 halogens, where Xis —H or a protecting group, or the aryl, heterocycle, —CH₂-heterocycleor —CH₂-aryl moieties are optionally independently substituted with 1, 2or 3 C₁₋₄ alkyl moieties or with 1, 2 or 3 C₁₋₄ alkoxy moieties at thearyl moiety or at the heterocycle, usually at a ring carbon. ExemplaryR²⁵ are —H, —CH₃, —C₂H₅, —C₃H₇, —C₄H₉, —C₆H₁₃, —C₆H₅, —C₆H₄OH,—C₆H₄OCH₃, —C₆H₄F, —CH₂—C₁₋₅ optionally substituted alkyl,—CH₂CH₂—(S)₀₋₁—C₁₋₄ optionally substituted alkyl and —CH₂CH₂—O—C₁₋₄optionally substituted alkyl.

For any formula 1, 2, 5, 6, 7, 8, 9 or 10 compounds, whenever a variablemoiety such as R⁷, R⁸ or R⁹ or a substitution at a variable groupincludes moieties such as —O—CHR¹⁰—, —NR^(PR)—CHR¹⁰—, or ═N— it isintended that such moieties can be present in either orientationrelative to the other ring atoms that may be present, i.e., —O—CHR¹⁰—,—NR^(PR)—CHR¹⁰—, —CHR¹⁰—O—, —CHR¹⁰—NR^(PR)—, ═N— and —N═ are allincluded, unless defined or implied otherwise by the structure.

Invention embodiments include a composition comprising a F1C and 1, 2,3, 4 or more nonaqueous liquid excipients. These compositions cancontain less than about 3% w/v water, less than about 2% w/v water, lessthan about 1.5% w/v water, less than about 1% w/v water, less than about0.8% w/v water, less than about 0.5% w/v water, less than about 0.3% w/vwater or less than about 0.1% w/v water. Typically, the nonaqueousliquid excipients include propylene glycol and a PEG or a PEG mixtureand can optionally include one or both of benzyl alcohol and benzylbenzoate.

Embodiments of F1Cs include or exclude any subset of compounds withinthe definition of formula 1, provided that at least one F1C remains. Forexample, a subset of F1Cs that are may be included, for example in theinvention nonaqueous formulations and in the invention intermittentdosing protocols and immune modulation methods, are (1) F1Cs where R² ishydroxyl, or a group that can hydrolyze or metabolize to hydroxyl orthiol, in either configuration and R⁵ and R⁶ are methyl in theα-configuration or (2) any 1, 2, 3, 4, 5, 6 or more of the F1Cs orgenera of compounds that are disclosed herein. Another group ofcompounds that are optionally excluded from F1Cs comprises one or allcompounds that are disclosed in one or more prior art references orpublications, e.g., one or more compounds that are disclosed in one ormore of the references cited herein, especially for those compounds thatcan render any claim or embodiment unpatentable for novelty, obviousnessand/or inventive step reasons.

Other embodiments of species and genera of F1Cs include compounds ofstructures B, C, D, E, F and G

where the dotted lines represent double or single bonds, each R^(10A),R^(10B), R^(10C), R^(10D), R^(10E) (when present), R^(10F), R^(10G) andR^(10H) is an independently selected single bonded R¹⁰ moiety in theα-configuration or the β-configuration, or each R^(10A), R^(10B),R^(10C) and R^(10D) is an independently selected double bonded R¹⁰moiety (e.g., ═O or ═CH₂), R^(1A) is a single bonded R¹ moiety in theα-configuration, or R^(1A) together with R¹ is a double bonded moiety(e.g., ═O, ═NOH, ═CH₂ or ═CH—CH₃), R^(2A) is a single bonded R² moietyin the α-configuration, or R^(2A) together with R² is a double bondedmoiety, R^(3B) is a single bonded R³ moiety in the β-configuration, orR^(3B) together with R³ is a double bonded moiety, or R^(3B) is absentif a double bond is present at the 16-17 position, R^(4A) is a singlebonded R⁴ moiety in the α-configuration, or R^(4A) together with R⁴ is adouble bonded moiety, or R^(4A) is absent if a double bond is present atthe 16-17 position, and R⁵, R⁶, R⁷, R⁸ and R⁹ are as previously defined.When a double bond is present at the 4-5 or the 5-6 positions, R^(10E)is absent. For these structures, R^(10A), R^(10B), R^(10C) and R^(10D)may be in the α,α, α,β, β,α, or β,β configurations respectively, whileR^(10E), R^(10F), R^(10G) and R^(10H) may be in the α,α,α,α, α,α,α,β,α,α,β,α, α,β,α,α, β,α,α,α, α,α,β,β, α,β,α,β, β,α,α,β, β,α,β,α, β,β,α,α,α,β,β,α, α,β,β,β, β,α,β,β, β,β,α,β, β,β,β,α or β,β,β,β configurationsrespectively, typically the α,β,α,α or β,β,α,α configurations.

Thus, when R^(10E), R^(10F), R^(10G) and R^(10H) respectively are in theα,β,α,α configurations and R^(10A) and R^(10B) or R^(10A) and R^(10C) orR^(10A) and R^(10D) or R^(10B) and R^(10C) or R^(10B) and R^(10D) orR^(10C) and R^(10D) are both in α-configurations exemplary B, C, D, E, Fand G structures include

Similarly, when R^(10E), R^(10F), R^(10G) and R^(10H) respectively arein the α,β,α,α configurations and R^(10A) and R^(10B) or R^(10A) andR^(10C) or R^(10A) and R^(10D) or R^(10B) and R^(10C) or R^(10B) andR^(10D) or R^(10C) and R^(10D) respectively are in the β,αconfigurations exemplary B, C, D, E, F and G structures include

When R^(10E), R^(10F), R^(10G) and R^(10H) respectively are in theα,β,α,α configurations and R^(10A) and R^(10B) or R^(10A) and R^(10C) orR^(10A) and R^(10D) or R^(10B) and R^(10C) or R^(10B) and R^(10D) orR^(10C) and R^(10D) respectively are in the α,β configurations exemplaryB, C, D, E, F and G structures include

When R^(10E), R^(10F), R^(10G) and R^(10H) respectively are in theα,β,α,α configurations and R^(10A) and R^(10B) or R^(10A) and R^(10C) orR^(10A) and R^(10D) or R^(10B) and R^(10C) or R^(10B) and R^(10D) orR^(10C) and R^(10D) respectively are in the β,β configurations exemplaryB, C, D, E, F and G structures include

When R^(10E), R^(10F), R^(10G) and R^(10H) respectively are in theβ,β,α,α configurations exemplary B, C, D, E, F and G structures include

When a double bond is present at the 5-6 position, and R^(10F), R^(10G)and R^(10H) respectively are in the β,α,α configurations exemplary B, C,D, E, F and G structures include

When a double bond is present at the 1-2 and 5-6 positions, and R^(10F),R^(10G) and R^(10H) respectively are in the β,α,α configurationsexemplary B, C, D, E, F and G structures include

When a double bond is present at the 5-6 and 16-17 positions, andR^(10F), R^(10G) and R^(10H) respectively are in the β,α,αconfigurations exemplary B, C, D, E, F and G structures include

When R⁶ and R^(10C) are linked through a —CH₂—O— moiety there is nodouble bond at the 5-6 position and exemplary F1C structures include

When adjacent variable groups are an epoxide or an optionallysubstituted cyclopropyl ring exemplary F1C structures include

wherein variable groups are independently selected and, when notspecified otherwise, are in the α- or β-configuration.

Substituents at the cyclopropyl ring include one or two halogen atoms,e.g., dichloro, dibromo or difluoro. Typically these F1C contain one ortwo epoxide or cyclopropyl moieties.

Other F1Cs and structures having B, C, D, E, F and G structures areapparent from the foregoing descriptions and variable group definitions.

Thus, exemplary F1C, e.g., 2, 5, 6, 7, 8, 9, 10, B, C, D, E, F and Gstructures are characterized as having the following:

(1) a double bond at the 5-6 position, no double bonds with R^(10E) atthe 5 position in the α-configuration, no double bonds with R^(10E) inthe β-configuration, a double bond at the 4-5 position, a double bond atthe 1-2 position with R^(10E) in the α-configuration, a double bond atthe 1-2 position with R^(10E) in the β-configuration, double bonds atthe 1-2 and 4-5 positions, double bonds at the 1-2 and 5-6 positions, adouble bond at the 16-17 position with R^(10E) in the α-configuration, adouble bond at the 16-17 position with R^(10E) in the β-configuration,double bonds at the 4-5 and 16-17 positions, double bonds at the 5-6 and16-17 positions, double bonds at the 1-2 and 16-17 positions withR^(10E) in the α-configuration, double bonds at the 1-2 and 16-17positions with R^(10E) in the β-configuration, double bonds at the 1-2,5-6 and 16-17 positions or double bonds at the 1-2, 4-5 and 16-17positions, and

(2) R^(10A), R^(10B), R^(10C) and R^(10D) are independently selected R¹⁰groups in the α,α, α,β, β,α or β,β configurations respectively, and

(3) R^(10E), R^(10F), R^(10G) and R^(10H) are independently selected R¹⁰groups in the α,α,α,α, α,α,α,β, α,α,β,α, α,β,α,α, β,α,α,α, α,α,β,β,α,β,α,β, β,α,α,β, β,α,β,α, β,β,α,α, α,β,β,α, α,β,β,β, β,α,β,β, β,β,α,β,β,β,β,α or β,β,β,β configurations respectively, and

(4) R^(1A), R^(2A), R^(3B) and R^(4A) are —H, R^(1A) is not —H andR^(2A), R^(3B) and R^(4A) are —H, R^(2A) is not —H and R^(1A), R^(3B)and R^(4A) are —H, R^(3B) is not —H and R^(1A), R^(2A) and R^(4A) are—H, R^(4A) is not —H and R^(1A), R^(2A) and R^(3B) are —H, R^(1A) andR^(2A) are not —H and R^(3B) and R^(4A) are —H, R^(1A) and R^(3B) arenot —H and R^(2A) and R^(4A) are —H, R^(1A) and R^(4A) are not —H andR^(2A) and R^(3B) are —H, R^(2A) and R^(3B) are not —H and R^(1A) andR^(4A) are —H, R^(2A) and R^(4A) are not —H and R^(1A) and R^(3B) are—H, R^(3B) and R^(4A) are not —H and R^(1A) and R^(2A) are —H, R^(1A),R^(2A) and R^(3B) are not —H and R^(4A) is —H, R^(1A), R^(2A) and R^(4A)are not —H and R^(3B) is —H, R^(1A), R^(3B) and R^(4A) are not —H andR^(2A) is —H, R^(2A), R^(3B) and R^(4A) are not —H and R^(1A) is —H,R^(1A), R^(2A), R^(3B) and R^(4A) are not —H, R^(1A) and R^(2A) are —Hand R^(3B) and R^(4A) are absent (i.e., a 16-17 double bond is present),R^(1A) is —H and R^(2A) is not —H and R^(3B) and R^(4A) are absent,R^(2A) is —H and R^(1A) is not —H and R^(3B) and R^(4A) are absent, or,R^(1A) and R^(2A) are not —H and R^(3B) and R^(4A) are absent, whereeach R^(1A), R^(2A), R^(3B) and R^(4A) are independently selected, and

(5) each R¹, R², R³ and R⁴ are independently selected.

For these exemplary formula B, C, D, E, F and G structures and any otherF1C structures disclosed herein, each R¹, R^(1A), R², R^(2A), R³,R^(3B), R⁴, R^(4A), R¹⁰, R^(10A), R^(10B), R^(10C), R^(10D), R^(10E),R^(10F) and R^(10G) are an independently selected atom or moiety asdescribed herein, e.g., —H, —OH, ═O, —SH, ═S, —F, —Cl, —Br, —I, —CN,—SCN, —N₃, —NH—C1-C8 optionally substituted alkyl, —N(C1-C8 optionallysubstituted alkyl)₂ where each optionally substituted alkyl moiety isthe same or different, protected ketone, e.g., ethylene ketal(—O—CH₂—CH₂—O—), —NO₂, —ONO₂, —(CH₂)_(n)—CH(O), —(CH₂)_(n)—COOH,—(CH₂)_(n)—COOR^(PR), —(CH₂)_(n)—NHCH₃, —(CH₂)_(n)—NHR^(PR),—(CH₂)_(n)—CH(S), —O—S(O)(O)—OH, —O—P(O)(O)—OH, where n is 0, 1, 2, 3,4, 5 or 6, —O-β-D-glucopyranosiduronate,—OP(O)(OH)—NH—C(═NH)—N(CH₃)—CH₂—C(O)OH, or a group such as:

optionally substituted alkyl, e.g., —CH₃, —C₂H₅, —CH₂CH₂CH₃,—CH₂CH₂CH₂CH₃, —CH₂CH₂OCH₂CH₃, —CH₂OH, —CH₂CH₂OH, —CHOHCH₃,—CH(OC(O)CH₃)—CH₃, —CH(OR^(PR))—CH₃, —CHOH—(CH₂)_(n)—OH,—CH(OR^(PR))—(CH₂)_(n)—OR^(PR), —CHOH—(CH₂)_(n)—CH₂OH,—CH(OR^(PR))—(CH₂)_(n)—CH₂OR^(PR), —CHOH—(CH₂)_(n)—CH₂SH,—CH(OR^(PR))—(CH₂)_(n)—CH₂SR^(PR), —CH₂—(CH₂)_(n)—OCH₃, —CF₃,—(CH₂)_(t)—CF₃, —(CH₂)_(t)—NH₂, —(CH₂)₂—NH₂, —(CH₂)₃—NH₂, —CH₂—NHCH₃,—(CH₂)₂—NHCH₃, —(CH₂)₃—NHCH₃, —(CH₂)_(t)—N(CH₃)₂, —(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—CH₂F, —(CH₂)_(n)—CH₂Cl, —(CH₂)_(n)—CH₂Br,—CH(CH₃)—(CH₂)₃—CH(CH₃)₂, —CH(CH₃)—(CH₂)_(n)—CH(CH₃)₂,—CH(CH₃)—(CH₂)₃—CH(CH₃)—CH₂OH, —CH(CH₃)—(CH₂)_(n)—CH(CH₃)—CH₂OH,—CH(CH₃)—(CH₂)₃—CH(CH₃)—CH₂F, —CH(CH₃)—(CH₂)_(n)—CH(CH₃)—CH₂F,—CH(CH₃)—(CH₂)₃—CH(CH₃)—CH₂Cl, —CH(CH₃)—(CH₂)_(n)—CH(CH₃)—CH₂Cl,—CH(CH₃)—(CH₂)₃—CH(CH₃)—CH₂Br, —CH(CH₃)—(CH₂)_(n)—CH(CH₃)—CH₂Br,—CH(CH₃)—(CH₂)₃—CH(CH₂F)₂, —CH(CH₃)—(CH₂)_(n)—CH(CH₂F)₂,—(CH₂)₃—CH(CH₃)₂, —(CH₂)_(n)—CH(CH₃)₂, —(CH₂)₃—CH(CH₃)—CH₂OH,—(CH₂)_(n)—CH(CH₃)—CH₂OH, —(CH₂)₃—CH(CH₃)—CH₂F, —(CH₂)_(n)—CH(CH₃)—CH₂F,—(CH₂)₃—CH(CH₃)—CH₂Cl, —(CH₂)_(n)—CH(CH₃)—CH₂Cl, —(CH₂)₃—CH(CH₃)—CH₂Br,—(CH₂)_(n)—CH(CH₃)—CH₂Br, —(CH₂)₃—CH(CH₂F)₂, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH(OH)CH₃, —(CH₂)_(n)—CH(CH₂F)₂,—CH(CH₃)—(CH₂)_(n)—CH(CH₂CH₃)—CH(CH₃)_(m)(CH₂R⁵¹)P, —C≡CH, —C≡CCH₃,—C≡CCF₃, —C≡CCl, —CH═CH₂, —CF═CF₂, —CF═CFCH₃, —CH═CHCH₃, —C(O)—NH—C₆H₅,—C(O)—NH—CH₃, —C(O)—NH—C₂H₅, —C(CH₃)═N—OH, —C(CH₃)═N—NH—C(O)—OC₂H₅,—C(CH₃)═N—NH—C(O)—OC₄H₉, —C(CH₃)═N—NH—C(O)—OC₆H₅, —CH₂—C₆H₅,—CH₂—C₆H₅(CH₂)_(n)—F, —C₆H₅, —C₆H₄(CH₂)_(n)—F, —C₆H₄(CH₂)_(n)—OH,—C₆H₄(CH₂)_(n)—C(O)OH, —C₆H₄(CH₂)_(n)—C(O)OCH₃, —CH═CH—(CH₂)_(n)—CH₃,—CH(CH₃)—(CH₂)_(n)—CH₂—C(H)_(q)(CH₃)_(m)(CH₂R⁵¹)_(p),—CH(CH₃)—(CH₂)_(n)—CH═C(CH₃)(CH₂OH), —CH(CH₂OH)—(CH₂)_(n)—CH═C(CH₃)₂,═CH—(CH₂)_(n)-R⁴⁵, ═CH—(CH₂)_(t)—(CH═CH)—R⁴⁵, ═C(CH₃)—CH₂—C(O)—N(C1-C6alkyl)₂, ═C(CH₃)—(CH₂)₂—C(O)—N(C1-C6 alkyl)₂, ═C(CH₃)—CH₂—C(O)—NH—C1-C6alkyl, ═C(CH₃)—(CH₂)₂—C(O)—NH—C1-C6 alkyl, ═C(CH₃)—CH₂—N(C1-C6 alkyl)₂,═C(CH₃)—(CH₂)₂—N(C1-C6 alkyl)₂, ═C(CH₃)—CH₂—NH—C1-C6 alkyl,═C(CH₃)—(CH₂)₂—NH—C1-C6 alkyl, ═CH—CH₂—C(O)—N(C1-C6 alkyl)₂,═CH—(CH₂)₂—C(O)—N(C1-C6 alkyl)₂, ═CH—CH₂—C(O)—NH—C1-C6 alkyl,═CH—(CH₂)₂—C(O)—NH—C1-C6 alkyl, ═CH—CH₂—N(C1-C6 alkyl)₂,═CH—(CH₂)₂—N(C1-C6 alkyl)₂, ═CH—CH₂—NH—C1-C6 alkyl, ═CH—(CH₂)₂—NH—C1-C6alkyl, ═C(CH₃)—CH₂—C(O)—NH₂, ═C(CH₃)—(CH₂)₂—C(O)—NH₂,═C(CH₃)—(CH₂)₂—NH₂, ═C(CH₃)—CH₂—NH₂, ═CH—CH₂—C(O)—NH₂,═CH—(CH₂)₂—C(O)—NH₂, ═CH—CH₂—NH₂ or ═CH—(CH₂)₂—NH₂, where R⁴⁵ is an R¹substituent disclosed herein, e.g., —H, —OH, —F, —Cl, —Br, —I, —OCH₃,—C(O)OH, —C(O)OCH₃, —OR^(PR), —SH, —SR^(PR), —NH₂—NH—C1-C8 optionallysubstituted alkyl, —N(C1-C8 optionally substituted alkyl)₂ where eachoptionally substituted alkyl moiety is the same or different, or—NHR^(PR), R⁵¹ independently are an R¹ substituent disclosed herein,e.g., an ester, —F, —Cl, —Br, —I, alkyl (e.g., —CH₃), an ether (e.g.,(—OCH₃), a thioether (e.g., (—SCH₃), an optionally substitutedheterocycle, —C(O)OH, —NH₂ or —CN, m is 0, 1, 2 or 3, n is 0, 1, 2, 3,4, 5 or 6, p is 0, 1, 2 or 3, q is 0, 1, 2 or 3, t is 1, 2, 3, 4, 5 or 6and R^(PR) are —H or independently selected protecting groups, or

optionally substituted alkenyl, e.g., ═CH₂, ═CH₂CH₃, ═CH—CH₂OH,═CH—(CH₂)_(n)—OR^(PR), —CH═CH₂, —CH═CHF, —CH═CHCl, —CH═CHBr, —CH═CHI,—CH═CH—(CH₂)_(n)—OH, —CH═CH—(CH₂)_(n)—F, —CH═CH—(CH₂)_(n)—Cl,—CH═CH—(CH₂)_(n)—Br, —CH═CH—(CH₂)_(n)-1, —CH═NCH₃, —CH═NR^(PR),—CH═N—CH₃, —CH═CH—CH₃, —CH═CH—(CH₂)_(n)—COOR^(PR),—CH═CH—(CH₂)_(n)—NHR^(PR), —CH═CH—CH₂—OR^(PR), —CH═CH—CH₂—CF₃,—CH═CH₂—CH₂-halogen, —CH═CH—(CH₂)_(n)—OCH₃,—CH═CH—(CH₂)_(n)—C(O)—O-optionally substituted alkyl,—CH═CH—(CH₂)_(n)—C(O)—S-optionally substituted alkyl,═CH—CH₂—(CH₂)_(n)—SR^(PR), ═CH—(CH₂)_(n)—C(O)NHR^(PR),═CH—(CH₂)_(n)—C(O)NHCH₃, ═CH—(CH₂)_(n)—C(O)NHC₂H₅, ═CH—CH₂CH₃,═CH—(CH₂)_(n)—CH(CH₃)₂, ═CH—(CH₂)_(n)—CH(CH₃)(CH₂OR^(PR)),═CH—(CH₂)_(n)—CH(CH₃)(CH₂C(O)OR^(PR)), ═CH—(CH₂)_(n)—OH,═CCH₃—(CH₂)_(n)—OR^(PR), ═CCH₃—(CH₂)_(n)—C(O)OR^(PR),═CCH₃—(CH₂)_(n)—C(O)NHR^(PR), ═CCH₃—(CH₂)_(n)-halogen, ═CH—CHOH—CH₂—OHor ═CH—CH₂CH₂-halogen, where R^(PR) is —H or a protecting group and n is0, 1, 2, 3, 4, 5 or 6, or

optionally substituted alkynyl, e.g., —C≡CH, —C≡C—(CH₂)_(m)—OH,—C≡C—halogen, —C≡C—CH₃, —C≡CCF₃, —C≡CCH₂F, —C≡CCH₂Cl, —C≡CCH₂Br,—C≡CCH₂I, —C≡C—CH₂OH, —C≡C—CH₂-halogen, —C≡C—CH₂—C(O)OR^(PR),—C≡C—CH₂—CH₃, —C≡CCH₂CF₃, —C≡C—CH₂—CH₂OH, —C≡C—CH₂—CH₂-halogen,—C≡C—(CH₂)_(n)—C₆H₅, —C≡C—(CH₂)_(n)—C₆H₄OH,—C≡C—(CH₂)_(n)—C₆H₄COOR^(PR), —C≡C—(CH₂)_(n)—C₆H₃(OH)₂,—C≡C—(CH₂)_(n)—C₆H₄F, —C≡C—(CH₂)_(n)—C₆H₄Br, —C≡C—CH₂—CH₂—C(O)OR^(PR),—C≡C—(CH₂)_(n)—CH₃, —C≡C—CH(CH₃)—(CH₂)_(n)—CH₃,—C≡C—(CH₂)_(n)—CHOR^(PR), —C≡C—CH(CH₃)—(CH₂)_(n)—CHOR^(PR),—C≡C—(CH₂)_(n)—CHCOOR^(PR), —C≡C—CH(CH₃)—(CH₂)_(n)—NHR^(PR),—C≡C—(CH₂)_(n)—NHR^(PR), —C≡C—(CH₂)_(n)—C(O)NH—(CH₂)_(n)—CH₃,—C≡C—C≡C—(CH₂)_(n)—CH₃, —C≡C—C≡C—(CH₂)_(n)-halogen,—C≡C—(CH₂)_(n)—OS(O)(O)—O—R^(PR), —C≡C—(CH₂)_(n)—OS(O)(O)—O-optionallysubstituted alkyl, —C≡C—C≡C—(CH₂)_(n)—OR^(PR) or—C≡C—CH(CH₃)—(CH₂)_(n)—CHOR^(PR), where n is 0, 1, 2, 3, 4, 5 or 6, m is1, 2, 3 or 4 and R^(PR) is —H or a protecting group, or

optionally substituted aryl, optionally substituted alkylaryl,optionally substituted alkenylaryl or optionally substitutedalkynylaryl, e.g., optionally substituted phenyl, optionally substitutedbenzyl, —(CH₂)_(n)—C₆H₄OH, —(CH₂)_(n)—C₆H₄OR^(PR), —(CH₂)_(n)—C₆H₃(OH)₂,—(CH₂)_(n)—C₆H₄F, —(CH₂)_(n)—C₆H₄Br, —(CH₂)_(n)—C₆H₄C(O)OR^(PR),—(CH₂)_(n)—C₆H₄C(O)SR^(PR), or analogs where the aromatic ring contains1, 2, 3 or 4 independently chosen substituents such as independentlychosen halogen, —OH, —SH, —NO₂, —CN, —SCN, —N₃, C1-C6 ester, C1-C6alkyl, C1-C6 ether, C1-C6 thioether, —OR^(PR), —(CH₂)_(n)—C(O)OR^(PR),—(CH₂)_(n)—NHR^(PR), —(CH₂)_(n)—OR^(PR) or—(CH₂)_(m)—O—(CH₂)_(m)—OR^(PR) where n is 0, 1, 2, 3, 4, 5 or 6, mindependently are 1, 2 or 3 and R^(PR) independently are —H or aprotecting group, or

ether, e.g., optionally substituted alkoxy, optionally substitutedalkenyloxy, optionally substituted alkynyloxy, optionally substitutedaryloxy, —OCH₃, —OC₂H₅, —OC₃H₇, —OC₄H₉, —OC₂H₃, —OC₃H₅, —OC₄H₇,—O—C(CH₃)₃, —OCH₂CH₂OH, —O(CH₂)₂—O—CH₃, —O(CH₂)₃—O—CH₃, —O—CH(CH₃)CH₃,—O—CH₂CH₂CH₃, —OCH₂CH₂F, —OCH₂CHF₂, —OCH₂CF₃, —OCH₂CH₂Cl, —OCH₂CH₂Br,—OCH₂CH₂I, —OCH₂CH₂CH₂F,—O—CH₂—CH(C(O)—NH—CH₂C(O)OH)—NH—C(O)—(CH₂)₂—CH(NH₂)—C(O)—OH,—O—(CH₂)₂—N⁺(CH₃)₃,), —O—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₃,—O—(CH₂)₀₋₃—(CH═CH)—(CH₂)₀₋₃—CH₂F, —O—(CH₂)₁₋₃—(C≡C)—(CH₂)₀₋₃—CH₃,—O—(CH₂)₁₋₃—(C≡C)—(CH₂)₀₋₃—CH₂F, —O—C₆H₅, —O—CH₂—C₆H₅, —O—C1-C20 organicmoiety where the organic moiety is, e.g., —CH₃, —C₂H₅, i-propyl,n-propyl, t-butyl, n-butyl, l-butyl, n-hexyl, n-octyl, n-decyl,—(CH₂)₁₋₈—OH, —CHO, —(CH₂)₁₋₈—NH₂, —(CH₂)₁₋₈—C(O)—OH,—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₃, —(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₂F,—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₂Br,—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—C(O)—OR^(PR),—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—NHR^(PR), —C(O)—CH₃, —C(O)—C₂H₅,—C(O)—C₆H₅, —CF₃, —CH₂CF₃ or —C₂F₅, wherein R^(PR) is —H or a protectinggroup, —O—C₁₋₁₀ optionally substituted alkyl such as i-propyl, n-propyl,t-butyl, n-butyl, n-hexyl, n-octyl, n-decyl, —(CH₂)₁₋₈—OH,—(CH₂)₁₋₈—NH₂, —(CH₂)₁₋₈—C(O)—OH, —(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₃,—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₂F, —(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₂Br,—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—C(O)—OR^(PR),—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—NHR^(PR), —CF₃ and —C₂F₅, wherein R^(PR)is —H or a protecting group, or

ester, e.g., —OC(O)CH₃, —OC(O)C₂H₅, —OC(O)C₂H₃, —OC(O)CH₂CH₂CH₃,—OC(O)CH(CH₃)₂, —O—C(O)—(CH₂)₂—C(O)OH, —O—C(O)—(CH₂)₂—C(O)OR^(PR),—O—C(O)—(CH₂)₃—C(O)OH, o—C(O)—(CH₂)₃—C(O)OR^(PR), —O—C(O)—(CH₂)₄—C(O)OH,—O—C(O)—(CH₂)₅—C(O)OH, —O—C(O)—(CH₂)₅—C(O)OR^(PR),—O—C(O)—(CH₂)₄—C(O)OR^(PR), —O—C(O)—(CH₂)₂—C(O)ONH₂,—C(O)—(CH₂)₂—C(O)ONHCH₃, —O—C(O)—(CH₂)₂—C(O)ONHC₂H₅,—O—C(O)—(CH₂)₂—C(O)ONHC₃H₇, —O—C(O)—(CH₂)₂—C(O)ONHC₃H₅,—O—C(O)—(CH₂)₂—C(O)ONHR^(PR), —O—C(O)—(CH₂)₂—C(O)ON(R^(PR))₂,—OC(O)—C(CH₃)₂—(CH₂)_(m)—CH₃, —OC(O)—(CH₂)_(m)—CH₃,—OC(O)—CH(CH₃)—(CH₂)_(m)—CH₃, —OC(O)—C(CF₃)₂—(CH₂)_(m)—CH₃,—OC(O)—CH(CF₃)—(CH₂)_(m)—CH₃, —OC(O)C₃H₇, —OC(O)C₃H₅, —OC(O)C₄H₉,—OC(O)C₄H₇, —OC(O)C(CH₃)₃, —OC(O)CH₂CH₂CH₂CH₃, —OC(O)C₆H₅,—OC(O)CH₂C₆H₅, —OC(O)—(CH₂)₂—C(O)OH, —OC(O)—(CH₂)₂—C(O)OCH₃,—OC(O)—(CH₂)₃—C(O)OH, —OC(O)—(CH₂)₃—C(O)OCH₃, —OC(O)—(CH₂)₄—C(O)OH,—OC(O)—(CH₂)₄—C(O)OCH₃, —OC(O)—CH(CH₃)—CH₂—C(O)OH,—OC(O)—CH(CH₃)—CH₂—C(O)OCH₃, —OC(O)—CH(CH₃)—(CH₂)₂—C(O)OH,—OC(O)—CH(CH₃)—(CH₂)₂—C(O)OCH₃, —OC(O)—C(CH₃)₂—CH₂—C(O)OH,—OC(O)—C(CH₃)₂—CH₂—C(O)OCH₃, —OC(O)—C(CH₃)₂—(CH₂)₂—C(O)OH,—OC(O)—C(CH₃)₂—(CH₂)₂—C(O)OCH₃, —OC(O)—(CH₂)₂—C(O)OH,—O—C(O)—C(O)—O—(CH₂)_(m)—CH₃, —C(O)—C(O)—O—(CH₂), —CH₂OH,—O—C(O)—(CH₂)_(n)—C(O)—O—(CH₂)_(m)—CH₃,—O—C(O)—(CH₂)_(n)—C(O)—O—(CH₂)—CH₂OH, —C(O)—CH(NH₂)—CH₂OH,—O—C(O)—CH₂—N(CH₃)—C(═NH)—NH₂,—O—C(O)—CH₂—NH—C(O)—CH(CH₂SH)—NH—C(O)—(CH₂)₂—CH(NH₂)—C(O)—OH, a C2-C20ester such as —O—C(O)—CH₃, —O—C(O)—CF₃, —O—C(O)—CCl₃, —O—C(O)—C₂H₅,—O—C(O)—C₄H₇, —O—C(O)—C₆H₅, —O—C(O)—(CH₂)₂—CH₃, —O—C(O)—(CH₂)₃—CH₃,—O—C(O)—(CH₂)₄—CH₃, —O—C(O)—(CH₂)₅—CH₃, —O—C(O)—(CH₂)₆—CH₃, —O—C(O)₂furanyl, —O—C(O)₂ thiophenyl, —O—C(O)₂ pyrrolyl, —O—C(O)₂ pyrimidinyl,—O—C(O)₃ pyrimidinyl, —O—C(O)₂ pyridyl, —O—C(O)₃ pyridyl,—O—C(O)-heterocycle, —O—C(O)—(CH₂)_(m)—C(O)O—C1-C10 optionallysubstituted alkyl, —O—C(O)—(CH₂)_(m)—C(O)O—C2-C10 optionally substitutedalkenyl, —O—C(O)—(CH₂)_(m)—O—(CH₂)_(m)—C(O)O—C1-C10 optionallysubstituted alkyl, —C(O)—(CH₂)_(m)—(CH₂)_(m)—C(O)OR^(PR),—O—C(O)—(CH₂)_(m)—S—(CH₂)_(m)—C(O)O—C1-C10 optionally substituted alkyl,—O—C(O)—(CH₂)_(m)—S—(CH₂)_(m)—C(O)OR^(PR),—O—C(O)—(CH₂)_(m)—NR^(PR)—(CH₂)_(m)—C(O)O—C1-C10 optionally substitutedalkyl, —O—C(O)—(CH₂)_(m)—NR^(PR)—(CH₂)_(m)—C(O)OR^(PR), —O—C(O)—C₁₋₁₂optionally substituted alkyl, —OC(O)—(CH₂)_(q)—C(O)OH,—OC(O)—(CH₂)_(q)—C(O)O—C₁₋₈ optionally substituted alkyl,—OC(O)—CH(CH₃)—(CH₂)_(q)—C(O)OH, —OC(O)—CH(CH₃)—(CH₂)_(q)—C(O)O—C₁₋₈optionally substituted alkyl, —OC(O)—C(CH₃)₂—(CH₂)_(q)—C(O)OH,—OC(O)—C(CH₃)₂—(CH₂)_(q)—C(O)O—Cl₈ optionally substituted alkyl,—OC(O)—C(C₂H₅)(CH₃)—(CH₂)_(q)—C(O)OH,—OC(O)—C(C₂H₅)(CH₃)—(CH₂)_(q)—C(O)O—Cl₈ optionally substituted alkyl,—OC(O)—C(C₂H₅)₂—(CH₂)_(q)—C(O)OH, —OC(O)—C(C₂H₅)₂—(CH₂)_(q)—C(O)O—C₁₋₈optionally substituted alkyl, —OC(O)—C(C₂H₅)(C₃H₇)—(CH₂)_(q)—C(O)OH,—OC(O)—C(C₂H₅)(C₃H₇)—(CH₂)_(q)—C(O)O—C₁₋₈ optionally substituted alkyl,where the optionally substituted alkyl optionally is methyl, ethyl,i-propyl, n-propyl, t-butyl, n-butyl, n-hexyl, n-octyl, n-decyl, vinyl,allyl, phenyl, monosubstituted phenyl, disubstituted phenyl,trisubstituted phenyl, —CH₂OH, —CH₂OR^(PR), —CH₂F, —CF₂H,—(CH₂)_(n)—CH₃, —(CH₂)_(n)—OH, —(CH₂)_(n)—F, —(CH₂)_(n)—Br,—(CH₂)_(n)—NH₂, —(CH₂)_(n)—C(O)—OR^(PR), —(CH₂)_(n)—O—CH₃,—(CH₂)_(n)—S—CH₃, —(CH₂)_(m)—(CH═CH)_(p)—(CH₂)_(q)—CH₃,—(CH₂)_(m)—(CH═CH)_(p)—(CH₂)_(q)—CH₂F,—(CH₂)_(m)—(CH═CH)_(p)—(CH₂)_(q)—CH₂Br,—(CH₂)_(m)—(CH═CH)_(p)—(CH₂)_(q)—C(O)—OR^(PR),—(CH₂)_(m)—(CH═CH)_(p)—(CH₂)_(q)—NHR^(PR), —CF₃, —CH₂CF₃ or —C₂F₅,wherein R^(PR) independently are —H, a protecting group such as C1-C10optionally substituted alkyl (e.g., —CH₃, —C₂H₅, —C₃H₆OH) or togetherare a protecting group, n is 1, 2, 3, 4, 5, 6, 7 or 8, m is 0, 1, 2, 3,4, 5 or 6, p is 0 or 1 and q is 0, 1, 2, 3, 4, 5 or 6, or

acyl, e.g., —C(O)OH, —C(O)—CH₂OH, —C(O)—CH₂F, —C(O)—CH₂Cl, —C(O)—CH₂Br,—C(O)—CH₂I, —C(O)—CH₂COOH, —C(O)—CH₂COOR^(PR), —C(O)—CH₃, —C(O)—CF₃,—C(O)—CH₂CF₃, —C(O)—CH(NH₂)—CH₂OH, —C(O)—CH₂—N(CH₃)—C(═NH)—NH₂,—C(O)—(CH₂)_(n)—CH₂OH, —C(O)—O—C(O)—C(CH₃)₃, —C(O)—O—C(O)—CH(CH₃)₂,—C(O)—O—C(O)—CH₃, —C(O)—O—C(O)—C₂H₅, —C(O)—(CH₂)_(n)—CH₂F,—C(O)—N(CH₃)₂, —C(O)—N(C₂H₅)₂, —C(O)—N(CH₃)(C₂H₅), —C(O)—NH[C(CH₃)₃],—C(O)—NH(CH₃), —C(O)NH₂, —C(O)—N(R^(PR))₂, —C(O)—(CH₂)_(n)—CH₂Cl,—C(O)—(CH₂)_(n)—CH₂Br, —C(O)—(CH₂)_(n)—CH₂—C(O)OH,—C(O)—(CH₂)_(n)—CH₂—NH₂, —C(O)—CH(CH₃)—(CH₂)₃—CH(CH₃)₂,—C(O)—CH(CH₃)—(CH₂)_(n)—CH(CH₃)₂, —C(O)—CH(CH₃)—(CH₂)₃—CH(CH₃)—CH₂OH,—C(O)—CH(CH₃)—(CH₂)_(n)—CH(CH₃)—CH₂OH,—C(O)—CH(CH₃)—(CH₂)₃—CH(CH₃)—CH₂F, —C(O)—CH(CH₃)—(CH₂)_(n)—CH(CH₃)—CH₂F,—C(O)—CH(CH₃)—(CH₂)₃—CH(CH₃)—CH₂Cl,—C(O)—CH(CH₃)—(CH₂)_(n)—CH(CH₃)—CH₂Cl, —C(O)CH₃, —C(O)CHO, —C(O)CH₂OH,—C(O)CH₂F, —C(O)CH₂Cl, —C(O)CH₂Br, —C(O)—CH₂OH, —C(O)—CH₂OR^(PR),—C(O)—(CH₂)_(n)—CH₂OH, —C(O)—(CH₂)_(n)—CH₂OR^(PR),—C(O)—S—(CH₂)_(n)—CH₂F, —C(O)—S—(CH₂)_(n)—CHF₂, —C(O)—S—(CH₂)_(n)—CF₃,—C(O)₂ furanyl, —C(O)-2 thiophenyl, —C(O)-2 pyrrolyl, —C(O)-2pyrimidinyl, —C(O)-3 pyrimidinyl, —C(O)-2 pyridyl, —C(O)-3 pyridyl,—C(O)-heterocycle, —C(O)—C1-C10-optionally substituted alkyl,—C(O)—NH-optionally substituted phenyl, —C(O)—NH-optionally substitutedheterocycle, —C(O)—(CH₂)_(n)-optionally substituted heterocycle,—C(O)—(CH₂)_(n)-optionally substituted phenyl, or —C(O)NR⁵⁰R⁵¹ whereR^(PR) independently are —H or a protecting group such as C1-C10optionally substituted alkyl, m is 0 or 1, n is 0, 1, 2, 3, 4, 5 or 6,and R⁵⁰ and R⁵¹ independently are —H, optionally substituted phenyl,optionally substituted phenylalkyl, optionally substituted alkyloptionally substituted alkenyl, or an optionally substitutedheterocycle, e.g., pyridyl, pyrrolyl, pyrimidyl, benzimidazolyl,benzoxazolyl, benzofuranyl, —CH₃, —C₂H₅, 2-, 3- or 4-fluorophenyl, 2-,3- or 4-chlorophenyl, 2-, 3- or 4-methoxyphenyl 2-, 3- or 4-methylphenylor 2-, 3- or 4-trifluoromethylphenyl, or

thioester, e.g., —SC(O)CH₃, —SC(O)C₂H₅, —SC(O)C₃H₇, —SC(O)C₄H₉,—SC(O)C₆H₅, —SC(O)CH₂C₆H₅, —C(O)SCH₃, —CS(O)C₂H₅, —CS(O)C₃H₇,—CS(O)C₄H₉, —CS(O)C₆H₅, —CS(O)CH₂C₆H₅, —S—C(O)—(CH₂)₂—C(O)OH,—S—C(O)—(CH₂)₂—C(O)OR^(PR), —S—C(O)—(CH₂)₃—C(O)OH,S—C(O)—(CH₂)₃—C(O)OR^(PR), —S—C(O)—(CH₂)₄—C(O)OH, —S—C(O)—(CH₂)₅—C(O)OH,—S—C(O)—(CH₂)₅—C(O)OR^(PR), —S—C(O)—(CH₂)₄—C(O)OR^(PR),—S—C(O)—CH(NH₂)—CH₂OH, —S—C(O)—CH₂—N(CH₃)—C(═NH)—NH₂,—S—C(O)—CH₂—NH—C(O)—CH(CH₂SH)—NH—C(O)—(CH₂)₂—CH(NH₂)—C(O)—OH), a C2-C20such as —S—C(O)—CH₃, —S—C(O)—CF₃, —S—C(O)—CCl₃, —S—C(O)—C₂H₅,—S—C(O)—C₆H₅, —S—C(O)—C₆H₄—OCH₃, —S—C(O)—C₆H₄—F, —S—C(O)—C₆H₄—Cl,—S—C(O)—C₆H₄—CH₃, —S—C(O)—C₁₋₁₂ optionally substituted alkyl,—S—C(O)—CH₂—NHR^(PR), —S—C(O)—CHOH—NHR^(PR),—S—C(O)—CH[(CH(OH)(CH₃)]—NHR^(PR), —S—C(O)—CH(CH₃)—NHR^(PR),—S—C(O)—CH[(CH₂)₂C(O)OR^(PR)]—NHR^(PR),—S—C(O)—CH(CH₂C(O)OR^(PR)—NHR^(PR), —S—C(O)—CH[(CH₂)₄NHR^(PR)]—NHR^(PR),—S—C(O)—CH[(CH₂)₂C(O)NHR^(PR)]—NHR^(PR),—S—C(O)—CH(CH₂C(O)NHR^(PR))—NHR^(PR), —S—C(O)—(CH₂)_(m)—C(O)ON(R^(PR))₂,—S—C(O)—(CH₂)_(m)—O—(CH₂)_(m)—C(O)OR^(PR),—S—C(O)—(CH₂)_(m)—S—(CH₂)_(m)—C(O)OR^(PR),—S—C(O)—(CH₂)_(m)—NR^(PR)—(CH₂)_(m)—C(O)OR^(PR),—S—C(O)—(CH₂)_(m)—O—(CH₂)—C(O)ON(R^(PR))₂,—S—C(O)—(CH₂)—O—(CH₂)_(m)—C(O)O—C1-C10 optionally substituted alkyl,—S—C(O)—(CH₂)_(m)—O—(CH₂)_(m)—C(O)OR^(PR),—S—C(O)—(CH₂)_(m)—S—(CH₂)_(m)—C(O)O—C1-C10 optionally substituted alkyl,—S—C(O)—(CH₂)—S—(CH₂), —C(O)OR^(PR), —S—C(O)—(CH₂)_(m)—NR^(PR)—(CH₂),—C(O)O—C1-C10 optionally substituted alkyl,—S—C(O)—(CH₂)_(m)—NR^(PR)—(CH₂)_(m)—C(O)OR^(PR), where the optionallysubstituted alkyl optionally is methyl, ethyl, i-propyl, n-propyl,t-butyl, n-butyl, n-hexyl, n-octyl, n-decyl, vinyl, allyl, phenyl,—CH₂OH, —CH₂F, —CF₂H, —(CH₂)_(n)—CH₃, —(CH₂)_(n)—OH, —(CH₂)_(n)—F,—(CH₂)_(n)—Br, —(CH₂)_(n)—NH₂, —(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—O—CH₃, —(CH₂)_(n)—S—CH₃,—(CH₂)_(m)—(CH═CH)_(p)—(CH₂)_(q)—CH₃,—(CH₂)_(m)—(CH═CH)_(p)—(CH₂)_(q)—CH₂F,—(CH₂)_(m)—(CH═CH)_(p)—(CH₂)_(q)—CH₂Br,—(CH₂)_(m)—(CH═CH)_(p)(CH₂)_(q)—C(O)—OR^(PR),—(CH₂)_(m)—(CH═CH)_(p)—(CH₂)_(q)—NHR^(PR), —CF₃, —CH₂CF₃, —C₂F₅, or athio analog of any ester moiety described herein, wherein R^(PR)independently are —H, a protecting group such as C1-C10 optionallysubstituted alkyl (e.g., —CH₃, —C₂H₅, —C₃H₆OH) or together are aprotecting group, n is 1, 2, 3, 4, 5, 6, 7 or 8, m is 0, 1, 2, 3, 4, 5or 6, p is 0 or 1 and q is 0, 1, 2, 3, 4, 5 or 6, or

thioether, e.g., —SCH₃, —SC₂H₅, —SC₃H₇, —SC₄H₉, —SC₂H₃, —SC₃H₅, —SC₄H₇,—SCH₂CH₂OH, —S—CH₂—CH(C(O)—NH—CH₂C(O)OH)—NH—C(O)—(CH₂)₂—CH(NH₂)—C(O)—OH,—S—(CH₂)₂—N⁺(CH₃)₃,), —SCH₂CH₂F, —SCH₂CHF₂, —SCH₂CF₃, —SCH₂CH₂Cl,—SCH₂CH₂Br, —SCH₂CH₂I, —SCH₂CH₂CH₂F, —S—SCH₃, —S—SC₂H₅, —S—SC₃H₇,—S—SC₄H₉, —S—C₁₋₂₀ organic moiety, —S—S—C₁₋₂₀ organic moiety,—S—CH₂—S—C₁₋₂₀ organic moiety, —S—(CH₂)₂—S—C₁₋₂₀ organic moiety,—S—(CH₂)₂—O—C₁₋₂₀ organic moiety, —S—S—CH₃, —S—S—C₂H₅, where the organicmoiety is any moiety described herein such as —CH₃, —C₂H₅, i-propyl,n-propyl, t-butyl, n-butyl, n-hexyl, n-octyl, n-decyl, —(CH₂)₁₋₈—OH,—(CH₂)₁₋₈—NH₂, —(CH₂)₁₋₈—C(O)—OH, —(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₃,—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₂F, —(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₂Br,—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—C(O)—OR^(PR),—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—NHR^(PR), —C(O)—CH₃—C(O)—C₂H₅, —C(O)—C₆H₅,—S—C₃₋₈ alkyl, —S—C₃₋₈ substituted alkyl, —CF₃, —CH₂CF₃ or —C₂F₅,wherein R^(PR) is —H or a protecting group, —S—C₁₋₁₀ optionallysubstituted alkyl such as i-propyl, n-propyl, t-butyl, n-butyl, n-hexyl,n-octyl, n-decyl, —(CH₂)₁₋₈—OH, —(CH₂)₁₋₈—NH₂, —(CH₂)₁₋₈—C(O)—OH,—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₃, —(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₂F,—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₂Br,—(CH₂)₀₋₃—(CH═CH)₀₋₃—(CH₂)—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—NHR^(PR), —CF₃,—C₂F₅, wherein R^(PR) is —H or a protecting group, or

thioacyl, e.g., —C(S)—(CH₂)_(n)—CH₂OH, —C(S)—(CH₂)_(n)—CH₂F,—C(S)—(CH₂)_(n)—CH₂Cl, —C(S)—(CH₂)_(n)—CH₂Br,—C(S)—CH(CH₃)—(CH₂)₃—CH(CH₃)₂, —C(S)—CH(CH₃)—(CH₂)_(n)—CH(CH₃)₂,—C(S)—CH(CH₃)—(CH₂)₃—CH(CH₃)—CH₂OH,—C(S)—CH(CH₃)—(CH₂)_(n)—CH(CH₃)—CH₂OH,—C(S)—CH(CH₃)—(CH₂)₃—CH(CH₃)—CH₂F, —C(S)—CH(CH₃)—(CH₂)_(n)—CH(CH₃)—CH₂F,—C(S)—CH(CH₃)—(CH₂)₃—CH(CH₃)—CH₂Cl,—C(S)—CH(CH₃)—(CH₂)_(n)—CH(CH₃)—CH₂Cl, —C(S)CH₃, —C(S)CH₂OH, —C(S)CH₂F,—C(S)CH₂Cl, —C(S)CH₂Br, —C(S)-2 furanyl, —C(S)-2 thiophenyl, —C(S)-2pyrrolyl, —C(S)-2 pyrimidinyl, —C(S)-3 pyrimidinyl, —C(S)-2 pyridyl,—C(S)-3 pyridyl, —C(S)-heterocycle, —C(S)—C1-C20-optionally substitutedalkyl or a thio analog of any acyl moiety described herein, where n is0, 1, 2, 3, 4, 5 or 6, or

optionally substituted amine, e.g., —NH₂, —NH₃ ⁺Cl⁻, —NH₃ ⁺Br⁻, —NH₃⁺I⁻, alkylamine, dialkylamine, —NH—CH₃, —N(CH₃)₂, —N⁺(CH₃)₃, —N⁺(C₂H₅)₃,—NHOH, —NHR^(PR)—N(R^(PR))₂, —NH—C(O)CH₃, —NH—C(O)CF₃, —N(C(O)CF₃)₂,—NH—C(O)CCl₃, —N(C(O)CCl₃)₂, —NH—C(O)C₆H₅, —N(C(O)C₆H₅)₂, —NH—C₂H₅,—N(C₂H₅)₂, —NH—CH₂OH, —NH—CH₂—CH₂OH, —NH—C₃H₇, —N(C₃H₇)₂,—NH—C(═NH)—N(CH₃)—CH₂—C(O)OR^(PR), —N(CH₃)₂, —N(C₂H₅)₂,—N(CH₃)(C₂H₅)—N(CH₂OH)(CH₃), —N═C[(CH₂)_(n)—H]—OH,—NH—NH—C(O)-optionally substituted alkyl, —NH—C(NH-optionallysubstituted alkyl)=N-optionally substituted alkyl,—N═C[(CH₂)_(n)—H]—O-optionally substituted alkyl, —NH-organic moiety,—NH—C(O)-organic moiety, e.g., —NH—C(O)—CH₃, —NH—(CH₂)_(n)-optionallysubstituted phenyl, —NH-optionally substituted alkyl, —N(optionallysubstituted alkyl)₂, —N(C(O)-optionally substituted alkyl)₂,—NH—C(O)-optionally substituted alkyl or —NH—(CH₂)_(n)-optionallysubstituted alkyl, wherein any of the phenyl or alkyl moieties are thesame or different and are optionally substituted with 1, 2, 3 or moreindependently selected with substituents described herein, e.g., —O—,—NH—, —S—, —F, —Cl, —Br, —I, —OH, —OR^(PR), —SH, —SR^(PR), —CH₃, —C₂H₅,—O—CH₃, —O—C₂H₅, —NO₂, —CN, —SCN, —NH₂, —C(O)OR^(PR) or—(CH₂)_(n)—C(O)—OR^(PR), wherein n is 0, 1, 2, 3 or 4, R^(PR)independently or together are —H or a protecting group and the organicmoiety is as described herein, e.g., optionally substituted alkyl or anester, or

optionally substituted amide, e.g., —C(O)—NH₂, —C(O)—NH—C(CH₃)₃,—C(O)—NH₂, —C(O)—NH—CH₃, —C(O)—NH—(CH₂)_(m)—CH₃, —C(O)—NH—(CH₂)_(m)—NH₂,—C(O)—NH—(CH₂)_(m)—NHR^(PR), —C(O)—NH—(CH₂)_(m)—NH—(CH₂)_(n)—CH₃,—NH—C(O)H, —NH—C(O)—CH₂—CH₂—C(O)OH, —NH—C(O)—CH₂—CH₂—C(O)OR^(PR),—NH—C(O)—(CH₂)_(m)—C(O)OH, —NH—C(O)—(CH₂)_(m)—C(O)OR^(PR), —NH—C(O)—CH₃,—NH—C(O)—(CH₂)_(m)—CH₃, —NH—C(O)—(CH₂)_(m)—NH₂,—NH—C(O)—(CH₂)_(m)—NHR^(PR), —NH—C(O)—O—C(CH₃)₃, —NH—C(O)—O—CH₃,—NH—C(O)—(CH₂)_(m)—NH—(CH₂)_(n)—CH₃, —C(O)—NH-organic moiety,—C(O)—NH-optionally substituted alkyl, —C(O)—NR⁴⁹—(O)_(p)-organicmoiety, —C(O)—NH—(O)_(p)—(CH₂)_(n)-optionally substituted phenyl,—C(O)—NH—(CH₂)_(n)—(O)_(p)-optionally substituted alkyl,—NH—C(O)—(O)_(p)-optionally substituted alkyl,—NH—C(S)—(O)_(p)-optionally substituted alkyl,—NH—C(O)—(S)_(p)-optionally substituted alkyl, wherein 1, 2 or more ofany organic, phenyl, alkyl, alkylene, e.g., —(CH₂)—, —(CH₂)_(m)— or—(CH₂)_(n)—, methyl, ethyl, n-butyl or t-butyl, moieties are optionallysubstituted with 1, 2, 3, 4, 5 or more independently selectedsubstituents described herein, e.g., —F, —Cl, —Br, —I, —OH, —CH₃, —C₂H₅,—O—CH₃, —O—C₂H₅, —NO₂, —CN, —SCN, —NH₂, —C(O)OR^(PR) or—(CH₂)₁₋₄—C(O)—OR^(PR), where R⁴⁹ is a protecting group, an organicmoiety comprising about 1-10 carbon atoms or R⁴⁹ together with theorganic moiety is a protecting group and the organic group optionally isoptionally substituted alkyl such as i-propyl, n-propyl, t-butyl,n-butyl, n-hexyl, n-octyl, n-decyl, —(CH₂)_(m)—OH, —(CH₂)_(m)—F,—(CH₂)_(m)—Cl, —(CH₂)_(m)—Br, —(CH₂)_(m)—NH₂, —(CH₂)_(m)—C(O)—OH,—(CH₂)_(m)—C(O)—H, —(CH₂)_(m)—C(O)—CH₃,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—NHR^(PR), —CF₃ or —C₂F₅, and R^(PR) is—H or a protecting group, optionally substituted alkyl moieties contain1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more carbon atoms and wherein mindependently are 1, 2, 3, 4, 5 or 6, n independently are 0, 1, 2, 3 or4 and p is 0 or 1, or

epoxide or optionally substituted cyclopropyl, when taken together witha hydrogen at an adjacent position on the steroid nucleus, usually wherethe epoxide or optionally substituted cyclopropyl bonds are both in theα-configuration or the β-configuration, e.g., one or more independentlyselected epoxide or optionally substituted cyclopropyl ring is presentat the 1-2 positions, the 2-3 positions, the 4-5 positions, the 5-6positions, the 10-11 positions, the 11-12 positions, the 15-16positions, the 16-17 positions, or at the 2-3 and 16-17 positions of thesteroid nucleus, or

—O—Si(C1-C6 alkyl)₃ where each alkyl is independently chosen, e.g.,—O—Si(CH₃)₃, —O—Si[C(CH₃)₃](CH₃)₂, —O—Si[C(CH₃)₃](C₂H₅)₂, or

phosphate ester, phosphoester, or an ether or thioether derivativethereof, e.g., —O—P(O)(OH)—OCH₃, —O—P(O)(OH)—OC₂H₅, —O—P(O)(OH)—OC₃H₇,—O—P(O)(OH)—OCH₂CH═CH₂, —O—P(O)(OCH₃)—OCH₃, —O—P(O)(OC₂H₅)—OC₂H₅,—O—P(O)(OH)—O—(CH₂)₂—N⁺(CH₃)₃, —O—P(O)(OH)—O—(CH₂)₂—NH₂),—O—P(O)(OH)—OH, —O—P(O)(OH)—SH, —O—P(O)(OR^(PR))—OH,—O—P(O)(OR^(PR))—SH, —S—P(O)(OH)—OH, —O—P(O)(OH)—S—(CH₂)₂—NH—(CH₂)₃—NH₂,—O—P(O)(OH)—O—CH₃, —O—P(O)(OCH₃)₂, —O—P(O)(OH)—O—C₂H₅, —O—P(O)(OC₂H₅)₂,—O—P(O)(OH)—O—C₃H₇, —O—P(O)(OC₃H₇)₂,—O—P—(O)(OH)—O—CH₂—CH(O—C(O)—(CH₂)_(y)(CH═CH)_(q)(CH₂)_(y)—CH₃)—CH₂—O—C(O)—(CH₂)_(y)(CH═CH)_(q)(CH₂)_(y)—CH₃,—O—P—(O)(OH)—O—CH₂—CH(O—C(O)—(CH₂)_(x)CH₃)—CH₂—O—C(O)—(CH₂)_(x)CH₃),—O—P—(O)(OH)—O—CH₂—CH(O—C(O)—(CH₂)₁₄CH₃)—CH₂—O—C(O)—(CH₂)₁₄CH₃),—O—P—(O)(OH)—O—CH₂—CH(O—C(O)—(CH₂)₁₂CH₃)—CH₂—O—C(O)—(CH₂)₁₂CH₃),—O—P(O)(OH)—O-optionally substituted alkyl, —S—P(O)(OH)—O-optionallysubstituted alkyl, —O—P(O)(OH)—S-optionally substituted alkyl,—O—P(O)(O-optionally substituted alkyl)-O-optionally substituted alkyl,—S—P(O)(O-optionally substituted alkyl)-O-optionally substituted alkyl,—O—P(O)(O-optionally substituted alkyl)-S-optionally substituted alkyl,where the optionally substituted alkyl moieties are as described hereinand are independently selected, e.g., i-propyl, n-propyl, t-butyl,n-butyl, n-hexyl, n-octyl, n-decyl, —(CH₂)_(m)—OH, —(CH₂)_(m)—F,—(CH₂)_(m)—Cl, —(CH₂)_(m)—Br, —(CH₂)_(m)—NH₂, —(CH₂)_(m)—C(O)—OH,—(CH₂)_(m)—C(O)—H, —(CH₂)_(m)—C(O)—CH₃,—(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₃, —(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(CH═CH)_(p)(CH₂)_(n)—C(O)—OR^(PR)—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—NHR^(PR),—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(C≡C)_(p)(C(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—NHR^(PR), —CF₃ or—C₂F₅, wherein R^(PR) is —H or a protecting group, m is 1, 2, 3, 4, 5 or6, n independently are 0, 1, 2, 3, 4, 5 or 6 and p is 0 or 1, q is 0 or1, x independently are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16 or 17, y independently are 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 andsubstituents bonded at double bonds are in the cis, trans or mixed cisand trans configuration, wherein In some embodiments, both n and p are 1or p is 1 and both n are 2 or one n is 1, the other n is 2 and p is 1,or

thionoester, e.g., a C2-C20 thionoester such as —O—C(S)—CH₃,—O—C(S)—CF₃, —O—C(S)—C₂H₅ or —O—C(S)—C₁₋₁₂ optionally substituted alkylwhere the optionally substituted alkyl optionally is i-propyl, n-propyl,t-butyl, n-butyl, n-hexyl, n-octyl, n-decyl, vinyl, allyl, phenyl,—CH₂OH, —CH₂F, —CF₂H, —(CH₂)_(n)—CH₃, —(CH₂)_(n)—OH, —(CH₂)_(n)—F,—(CH₂)_(n)—Br, —(CH₂)_(n)—NH₂, —(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—O—CH₃, —(CH₂)_(n)—S—CH₃,—(CH₂)_(m)—(CH═CH)_(p)—(CH₂)_(q)—CH₃,—(CH₂)_(m)—(CH═CH)_(p)—(CH₂)_(q)—CH₂F,—(CH₂)_(m)—(CH═CH)_(p)—(CH₂)_(q)—CH₂Br,—(CH₂)_(m)—(CH═CH)_(p)—(CH₂)_(q)—C(O)—OR^(PR),—(CH₂)_(m)—(CH═CH)_(p)—(CH₂)_(q)—NHR^(PR), —CF₃, —CH₂CF₃ or —C₂F₅,wherein R^(PR) is —H or a protecting group, n is 1, 2, 3, 4, 5, 6, 7 or8, m is 0, 1, 2, 3, 4, 5 or 6, p is 0 or 1 and q is 0, 1, 2, 3, 4, 5 or6, or

amino acid or peptide, e.g., a dipeptide, —O—C(O)—CH₂—NHR^(PR),—O—C(O)—CHOH—NHR^(PR), —O—C(O)—CH[(CH(OH)(CH₃)]—NHR^(PR),—O—C(O)—CH(CH₃)—NHR^(PR), —O—C(O)—CH[(CH₂)₂C(O)OR^(PR)]—NHR^(PR),—O—C(O)—CH(CH₂C(O)OR^(PR)—NHR^(PR), —O—C(O)—CH[(CH₂)₄NHR^(PR)]—NHR^(PR),—O—C(O)—CH[(CH₂)₂C(O)NHR^(PR)]—NHR^(PR),—O—C(O)—CH(CH₂C(O)NHR^(PR))—NHR^(PR), —O—C(O)—CHR⁴²—NHR^(PR),—NH—(CH₂)₁₋₄—C(O)OR⁴⁶ or —O—C(O)—(CH₂)₁₋₄—NHR⁴⁷ where R⁴² is —H, —CH₃,—C₂H₅, —(CH₂)_(n)—C(O)—OR^(PR), —CH₂—C(O)—OH, —CH₂—C(O)—NHR^(PR), —CH₂F,—CH₂Cl, —CH₂Br, —CHOH—CH₃ or —CH₂OH, R⁴⁶ is —H, optionally substitutedalkyl (e.g., —CH₃, —C₂H₅, —C₂H₃, —C₃H₇, —C₃H₅, —(CH₂)₁₋₈—OH,—(CH₂)₁₋₈—NH₂, —(CH₂)₁₋₈—C(O)—OH, —(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₃,—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₂F, —(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₂Br,—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—C(O)—OH,—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—NH₂, —CF₃ or —C₂F₅) or a protecting group(e.g., t-butyl, phenyl, benzyl or substituted phenyl), R⁴⁷ is —H,optionally substituted alkyl (e.g., —CH₃, —C₂H₅, —C₂H₃, —C₃H₇, —C₃H₅,—(CH₂)₁₋₈—OH, —(CH₂)₁₋₈—NH₂, —(CH₂)₁₋₈—C(O)—OH,—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₃, —(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₂F,—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—CH₂Br,—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—C(O)—OH,—(CH₂)₀₋₃—(CH═CH)₀₋₁—(CH₂)₀₋₃—NH₂, —CF₃ or —C₂F₅) or a protecting group(e.g., t-butyl, phenyl, benzyl or substituted phenyl) and R^(PR) is —Hor an independently selected protecting group such as C1-C8 optionallysubstituted alkyl and n is 0, 1, 2, or 3, or

optionally substituted heterocycle or —O—[C(O)]_(m)—(CH₂)_(n)-optionallysubstituted heterocycle, —(CH₂)_(n)-optionally substituted heterocycle,e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl,3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl,3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl or 1-piperidinyl, wherein m is 0 or 1 and n is 0, 1, 2 or3,e.g., m and n are both 0, m is 1 and n is 0, m is 0 and n is 1, m andn are both 1, or

carboxyl which is optionally substituted, e.g., —C(O)OH, —C(O)OR^(PR),—C(O)OM, —C(O)O—CH₃, —C(O)—O—(CH₂)_(n)—CH₃,—C(O)—O—CH(CH₃)—(CH₂)_(n)—CH₃, —C(O)—O—C(CH₃)₂—(CH₂)_(n)—CH₃,—C(O)—O—(CH₂)_(n)—C(O)OR^(PR), —C(O)—O—CH(CH₃)—(CH₂)_(n)—C(O)OR^(PR),—C(O)—O—C(CH₃)₂—(CH₂)_(n)—C(O)—O—(CH₂)_(n)—CH₂OR^(PR),—C(O)—O—CH(CH₃)—(CH₂)_(n)—CH₂OR^(PR),—C(O)—O—C(CH₃)₂—(CH₂)_(n)—CH₂OR^(PR), —C(O)—O—(CH₂)_(n)—CH₂NHR^(PR),—C(O)—O—CH(CH₃)—(CH₂)_(n)—CH₂NHR^(PR),—C(O)—O—C(CH₃)₂—(CH₂)_(n)—(CH₂)_(n)—CH₂NHR^(PR),—C(O)—O—(CH₂)_(n)—CH₂SR^(PR), —C(O)—O—CH(CH₃)—(CH₂)_(n)—CH₂SR^(PR),—C(O)—O—C(CH₃)₂—(CH₂)_(n)—CH₂SR^(PR), —C(O)O-organic moiety,—C(O)O—(CH₂)_(n)-optionally substituted phenyl or—C(O)O—(CH₂)_(n)-optionally substituted alkyl, wherein the phenyl oralkyl moieties are optionally substituted with 1, 2 or 3 independentlyselected with substituents described herein, e.g., —F, —Cl, —Br, —I,—OH, —CH₃, —C₂H₅, —O—CH₃, —O—C₂H₅, —NO₂, —CN, —SCN, —NH₂, —C(O)OR^(PR)or —(CH₂)₁₋₄—C(O)—OR^(PR), where n is 0, 1, 2, 3, 4, 5 or 6, R^(PR) is—H or a protecting group such as methyl, ethyl, propyl or butyl, and Mis a metal such as an alkali metal, e.g., Li⁺, Na⁺ or K⁺ or M is anothercounter ion such as an ammonium ion, or

carbonate, e.g., —O—C(O)—O—CH₃, —O—C(O)—O—(CH₂)_(n)—CH₃,—O—C(O)—O—CH(CH₃)—(CH₂)_(n)—CH₃, —O—C(O)—O—CH₂-halogen,—O—C(O)—O—(CH₂)_(n)—CH₂-halogen,—O—C(O)—O—CH(CH₃)—(CH₂)_(n)—CH₂-halogen,—O—C(O)—O—C(CH₃)₂—(CH₂)_(n)—CH₃, —O—C(O)—O—(CH₂)_(n)—C(O)OR^(PR),—O—C(O)—O—CH(CH₃)(CH₂)_(n)C(O)OR^(PR),—O—C(O)—O—C(CH₃)₂—(CH₂)_(n)—C(O)OR^(PR), —C(O)—OR^(PR),—O—C(O)—O—CH(CH₃)—(CH₂)_(n)—CH₂OR^(PR),—O—C(O)—O—C(CH₃)₂—O—C(O)—O—C(CH₃)₂—(CH₂)_(n)—CH₂NHR^(PR),—O—C(O)—O—CH(CH₃)—(CH₂)_(n)—CH₂SR^(PR),—O—C(O)—O—C(CH₃)₂—(CH₂)_(n)—CH₂SR^(PR), —O—C(O)—O-organic moiety,—O—C(O)—O(CH₂)_(n)-optionally substituted phenyl or—C(O)—O—(CH₂)_(n)-optionally substituted alkyl, wherein the phenyl oralkyl moieties are optionally substituted with 1, 2 or 3, 4 or moreindependently selected with substituents described herein, e.g., —F,—Cl, —Br, —I, —OH, —CH₃, —C₂H₅, —O—CH₃, —O—C₂H₅, —NO₂, —CN, —SCN, —NH₂,—C(O)OR^(PR) or —(CH₂)₁₋₄—C(O)—OR^(PR), and wherein n is 0, 1, 2, 3, 4,5 or 6 and R^(PR) is —H or a protecting group, or

carbamate, e.g., —O—C(O)—NH₂, —O—C(O)—NH—CH₃, —O—C(O)—NH—C₂H₅,—O—C(O)—NH—C₃H₇, —O—C(O)—NH—C₄H₉, —O—C(O)—NH—C₂H₃, —O—C(O)—NH—C₃H₅,—O—C(O)—NH—C₄H₇, —O—C(O)—NHR^(PR), —O—C(O)—N[(CH₂)_(n)CH₃]—CH₃,—O—C(O)—N[(CH₂)_(n)CH₃]—C₂H₅, —O—C(O)—N[(CH₂)_(n)CH₃]—C₃H₇,—O—C(O)—N[(CH₂)_(n)CH₃]—C₄H₉, —O—C(O)—N[(CH₂)_(n)CH₃]—C₂H₃,—O—C(O)—N[(CH₂)_(n)CH₃]—C₃H₅, —O—C(O)—N[(CH₂)_(n)CH₃]—C₄H₇,—O—C(O)—NH-organic moiety, —O—C(O)—NR⁴⁸-organic moiety,—NH—C(O)—O-organic moiety, —NR⁴⁸—C(O)—O-organic moiety, wherein theorganic moiety is as described herein, e.g., it optionally comprisesabout 1-20 carbon atoms, and wherein R⁴⁸ is —H, a protecting group, anorganic moiety or R⁴⁸ together with the organic moiety is a protectinggroup and the organic moiety optionally is optionally substituted alkylsuch as i-propyl, n-propyl, t-butyl, n-butyl, n-hexyl, n-octyl, n-decyl,—(CH₂)_(m)—OH, —(CH₂)_(m)—F, —(CH₂)_(m)—Cl, —(CH₂)_(m)—Br,—(CH₂)_(m)—NH₂, —(CH₂)_(m)—C(O)—OH, —(CH₂)_(m)—C(O)—H,—(CH₂)_(m)—C(O)—CH₃, —(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—C(O)—OR^(PR)—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—NHR^(PR),—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—NHR^(PR), —CF₃ or —C₂F₅, wherein R^(PR)is —H or a protecting group, m is 1, 2, 3, 4, 5 or 6, n independentlyare 0, 1, 2, 3, 4, 5 or 6 and p is 0 or 1, e.g., both n and p are 1 or pis 1 and both n are 2 or one n is 1, the other n is 2 and p is 1, or

phosphothioester or thiophosphate or an ether or thioether derivativethereof, e.g., —O—P(S)(OH)—OH, —O—P(S)(OH)—SH, —O—P(S)(OR^(PR))—OH,—O—P(S)(OR^(PR))—SH, —S—P(S)(OH)—OH, —O—P(S)(OH)—O—CH₃,—O—P(S)(OH)—O—C₂H₅, —O—P(S)(OH)—O—C₃H₇, —O—P(S)(OH)—O-optionallysubstituted alkyl, —S—P(S)(OH)—O-optionally substituted alkyl,—O—P(S)(OH)—S-optionally substituted alkyl, —O—P(S)(O-optionallysubstituted alkyl)-O-optionally substituted alkyl, —S—P(S)(O-optionallysubstituted alkyl)-O-optionally substituted alkyl, —O—P(S)(O-optionallysubstituted alkyl)-S-optionally substituted alkyl, where the optionallysubstituted alkyl moieties are as described herein and are independentlyselected, e.g., i-propyl, n-propyl, t-butyl, n-butyl, n-hexyl, n-octyl,n-decyl, —(CH₂)_(m)—OH, —(CH₂)_(m)—F, —(CH₂)_(m)—Cl, —(CH₂)_(m)—Br,—(CH₂)_(m)—NH₂, —(CH₂)_(m)—C(O)—OH, —(CH₂)_(m)—C(O)—H,—(CH₂)_(m)—C(O)—CH₃, —(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—NHR^(PR),—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—NHR^(PR), —CF₃ or —C₂F₅, wherein R^(PR)is —H or a protecting group, m is 1, 2, 3, 4, 5 or 6, n independentlyare 0, 1, 2, 3, 4, 5 or 6 and p is 0 or 1, e.g., both n and p are 1 or pis 1 and both n are 2 or one n is 1, the other n is 2 and p is 1, or

phosphonoester, phosphonate or an ether or thioether derivative thereof,e.g., —P(O)(OH)—OH, —P(O)(OH)—SH, —P(O)(OR^(PR))—OH, —P(O)(OR^(PR))—SH,—P(O)(OH)—OH, —P(O)(OH)—O—CH₃, —P(O)(OH)—O—C₂H₅, —P(O)(OH)—O—C₃H₇,—O—P(O)(OH)—H, —S—P(O)(OH)—H, —O—P(O)(OR^(PR))—H, —S—P(O)(OR^(PR))—H,—O—P(O)(OH)—CH₃, —O—P(O)(OH)—C₂H₅, —O—P(O)(OH)—C₃H₇,—O—P(O)(OH)-optionally substituted alkyl, —S—P(O)(OH)-optionallysubstituted alkyl, —P(O)(OH)—O-optionally substituted alkyl,—P(O)(OH)—S-optionally substituted alkyl, —P(O)(O-optionally substitutedalkyl)-O-optionally substituted alkyl, —P(O)(O-optionally substitutedalkyl)-S-optionally substituted alkyl, where the optionally substitutedalkyl moieties are as described herein and are independently selected,e.g., i-propyl, n-propyl, t-butyl, n-butyl, n-hexyl, n-octyl, n-decyl,—(CH₂)_(m)—OH, —(CH₂)_(m)—F, —(CH₂)_(m)—Cl, —(CH₂)_(m)—Br,—(CH₂)_(m)—NH₂, —(CH₂)_(m)—C(O)—OH, —(CH₂)_(m)—C(O)—H,—(CH₂)_(m)—C(O)—CH₃, —(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—NHR^(PR),—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—NHR^(PR), —CF₃ or —C₂F₅, wherein R^(PR)is —H or a protecting group, m is 1, 2, 3, 4, 5 or 6, n independentlyare 0, 1, 2, 3, 4, 5 or 6 and p is 0 or 1, e.g., both n and p are 1 or pis 1 and both n are 2 or one n is 1, the other n is 2 and p is 1, or

sulfate ester or an ether or thioether derivative thereof, e.g.,—O—S(O)(O)—OH, —O—S(O)(O)—SH, —O—S(O)(O)—OR^(PR), —O—S(O)(O)—O—CH₃,—O—S(O)(O)—O—C₂H₅, —O—S(O)(O)—O—C₃H₇, —O—S(O)(O)—S—CH₃,—O—S—(O)(O)—O—CH₂—CH(O—C(O)—(CH₂)_(y)(CH═CH)_(q)(CH₂)_(y)—CH₃)—CH₂—O—C(O)—(CH₂)_(y)(CH═CH)_(q)(CH₂)_(y)—CH₃,—O—S—(O)(O)—O—CH₂—CH(O—C(O)—(CH₂)_(x)CH₃)—CH₂—O—C(O)—(CH₂)_(x)CH₃),—O—S—(O)(O)—O—CH₂—CH(O—C(O)—(CH₂)₁₄CH₃)—CH₂—O—C(O)—(CH₂)₁₄CH₃),—O—S—(O)(O)—O—CH₂—CH(O—C(O)—(CH₂)₁₂CH₃)—CH₂—O—C(O)—(CH₂)₁₂CH₃),—O—S(O)(O)—O-optionally substituted alkyl, —O—S(O)(OH)—S-optionallysubstituted alkyl, where the optionally substituted alkyl moiety is asdescribed herein, e.g., i-propyl, n-propyl, t-butyl, n-butyl, n-hexyl,n-octyl, n-decyl, —(CH₂)_(m)—OH, —(CH₂)_(m)—F, —(CH₂)_(m)—Cl,—(CH₂)_(m)—Br, —(CH₂)_(m)—NH₂, —(CH₂)_(m)—C(O)—OH, —(CH₂)_(m)—C(O)—H,—(CH₂)_(m)—C(O)—CH₃, —(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—NHR^(PR),—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—NHR^(PR), —CF₃ or —C₂F₅, wherein R^(PR)is —H or a protecting group, m is 1, 2, 3, 4, 5 or 6, n independentlyare 0, 1, 2, 3, 4, 5 or 6, p is 0 or 1, q is 0 or 1, x independently are0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17, yindependently are 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 and substituents bondedat double bonds are in the cis, trans or mixed cis and transconfiguration, wherein In some embodiments, both n and p are 1 or p is 1and both n are 2 or one n is 1, the other n is 2 and p is 1, or

optionally substituted oxime, e.g., ═NOH, ═NOCH₃, ═NOC₂H₅, ═NOC₃H₇,═N—(CH₂)_(n)—(X)_(q)—(CH₂)_(n)-optionally substituted alkyl, where X is—O—, —C(O)—, —S— or —NH— and the optionally substituted alkyl moiety isas described herein, e.g., i-propyl, n-propyl, t-butyl, n-butyl,n-hexyl, n-octyl, n-decyl, —(CH₂)_(m)—OH, —(CH₂)_(m)—F, —(CH₂)_(m)—Cl,—(CH₂)_(m)—Br, —(CH₂)_(m)—NH₂, —(CH₂)_(m)—C(O)—OH, —(CH₂)_(m)—C(O)—H,—(CH₂)_(m)—C(O)—CH₃, —(CH₂)_(m)-heterocycle,—(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₃, —(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—NHR^(PR),—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—NHR^(PR), —CF₃ or —C₂F₅, wherein R^(PR)is —H or a protecting group, m is 1, 2, 3, 4, 5 or 6, n independentlyare 0, 1, 2, 3, 4, 5 or 6, p is 0 or 1, and q is 0 or 1, e.g., both nand p are 1 or p is 1 and both n are 2 or one n is 1, the other n is 2and p is 1, or

sulfite ester, sulfite ether, sulfite or sulfoxide, e.g., —O—S(O)—OH,—O—S(O)—OR^(PR), —O—S(O)—O—CH₃, —O—S(O)—O—C₂H₅, —O—S(O)—O—C₃H₇,—O—S(O)—O-organic moiety, —O—S(O)—O-optionally substituted alkyl,—S(O)—O—CH₃, —S(O)—O—C₂H₅, —S(O)—O—C₃H₇, —S(O)-organic moiety,—S(O)-optionally substituted alkyl, where the optionally substitutedalkyl moiety is as described herein, e.g., i-propyl, n-propyl, t-butyl,n-butyl, n-hexyl, n-octyl, n-decyl, —(CH₂)_(m)—OH, —(CH₂)_(m)—F,—(CH₂)_(m)—Cl, —(CH₂)_(m)—Br, —(CH₂)_(m)—NH₂, —(CH₂)_(m)—C(O)—OH,—(CH₂)_(m)—C(O)—H, —(CH₂)_(m)—C(O)—CH₃,—(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₃, —(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—NHR^(PR),—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—NHR^(PR), —CF₃ or —C₂F₅, wherein R^(PR)is —H or a protecting group, m is 1, 2, 3, 4, 5 or 6, n independentlyare 0, 1, 2, 3, 4, 5 or 6 and p is 0 or 1, e.g., both n and p are 1 or pis 1 and both n are 2 or one n is 1, the other n is 2 and p is 1, andthe organic moiety is as described herein, or

sulfonamide or a sulfonamide derivative, e.g., —S(O)(O)—NH₂,—S(O)(O)—NHR^(PR), —S(O)(O)—NH-optionally substituted alkyl,—NH—S(O)(O)-optionally substituted alkyl, —S(O)(O)—NH—CH₃,—S(O)(O)—NH—C₂H₅, —S(O)(O)—NH—C₃H₇, —NH—S(O)(O)—CH₃, —NH—S(O)(O)—C₂H₅,—NH—S(O)(O)—C₃H₇, where the optionally substituted alkyl moiety is asdescribed herein, e.g., i-propyl, n-propyl, t-butyl, n-butyl, n-hexyl,n-octyl, n-decyl, —(CH₂)_(m)—OH, —(CH₂)_(m)—F, —(CH₂)_(m)—Cl,—(CH₂)_(m)—Br, —(CH₂)_(m)—NH₂, —(CH₂)_(m)—C(O)—OH, —(CH₂)_(m)—C(O)—H,—(CH₂)_(m)—C(O)—CH₃, —(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—NHR^(PR),—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—C(O)—OR^(PR),—(C□C)_(p)—(CH₂)_(n)—NHR^(PR), —CF₃ or —C₂F₅, wherein R^(PR) is —H or aprotecting group, m is 1, 2, 3, 4, 5 or 6, n independently are 0, 1, 2,3, 4, 5 or 6 and p is 0 or 1, e.g., both n and p are 1 or p is 1 andboth n are 2 or one n is 1, the other n is 2 and p is 1, or

sulfamate or a sulfamate derivative, e.g., —O—S(O)(O)—NH₂,—O—S(O)(O)—NHR^(PR), —O—S(O)(O)—N(RD)₂, —O—S(O)(O)—NH-optionallysubstituted alkyl, —NH—S(O)(O)—O-optionally substituted alkyl,—O—S(O)(O)—NH—C(O)—CH₃, —O—S(O)(O)—NH—C(O)-optionally substituted alkyl,—O—S(O)(O)—NH—CH₃, —O—S(O)(O)—NH—C₂H₅, —O—S(O)(O)—NH—C₃H₇,—O—S(O)(O)—N(C(O)-optionally substituted alkyl)—R⁵²,—O—S(O)(O)—N(C(O)—N-optionally substituted alkyl)—R⁵²,—NH—S(O)(O)—O—CH₃, —NH—S(O)(O)—O—C₂H₅, —NH—S(O)(O)—O—C₃H₇,—NH—S(O)(O)—O-optionally substituted alkyl, where any optionallysubstituted alkyl moiety is as described herein, e.g., i-propyl,n-propyl, t-butyl, n-butyl, n-hexyl, n-octyl, n-decyl, —(CH₂)_(m)—OH,—(CH₂)_(m)—F, —(CH₂)_(m)—Cl, —(CH₂)_(m)—Br, —(CH₂)_(m)—NH₂,—(CH₂)_(m)—C(O)—OH, —(CH₂)_(m)—C(O)—H, —(CH₂)_(m)—C(O)—CH₃,—(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₃, —(CH₂)_(n)—(O)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—C(O)—OR^(PR),—(CH₂)_(n)—(CH═CH)_(p)—(CH₂)_(n)—NHR^(PR),—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₃,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂OH,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂F,—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—CH₂Br,—(CH₂)_(n)(C≡C)_(p)—(CH₂)_(n)—C(O)OR^(PR),—(CH₂)_(n)—(C≡C)_(p)—(CH₂)_(n)—NHR^(PR), —CF₃ or —C₂F₅, wherein R^(PR)is —H or a protecting group, RD independently are —H, optionallysubstituted alkyl (e.g., —CH₃, —C₂H₅, —C₃H₇, —CHO, —CH₂OH), acyl,benzoyl or benzyl, R⁵² is —H, optionally substituted alkyl, —COOH,—COOR^(PR), —COO-optionally substituted alkyl or —C(O)—N(R⁵³)₂, R⁵³independently are —H, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted alkylaryl or optionallysubstituted arylalkyl, or both R⁵³ together with the nitrogen atom towhich they are bonded are an N-containing ring such as morpholino or aC2-C6 polyemthyleneimino residue, m is 1, 2, 3, 4, 5 or 6, nindependently are 0, 1, 2, 3, 4, 5 or 6 and p is 0 or 1, e.g., both nand p are 1 or p is 1 and both n are 2 or one n is 1, the other n is 2and p is 1, or

a sulfonate, a sulfamide, a sulfinamide or a sulfurous diamide, e.g.,—O—S(O)(O)—CH₂-optionally substituted alkyl, —O—S(O)(O)-optionallysubstituted alkyl, —NH—S(O)(O)—NHR^(PR), —NH—S(O)(O)—NH-optionallysubstituted alkyl, —NH—S(O)—NHR^(PR), —NH—S(O)—NH-optionally substitutedalkyl, —S(O)—NHR^(PR), —S(O)—NHCH₃, —S(O)—N(CH₃)₂, —S(O)—NHC₂H₅,—S(O)—NH-optionally substituted alkyl, —NH—S(O)—NHR^(PR),—NH—S(O)—NHCH₃, —NH—S(O)—NHC₂H₅ or —NH—S(O)—NH-optionally substitutedalkyl, or

a monosaccharide, e.g., a D-, L- or DL-mixture of glucose, fructose,mannose, idose, galactose, allose, gulose, altrose, talose, fucose,erythrose, threose, lyxose, erythrulose, ribulose, xylulose, ribose,arabinose, xylose, psicose, sorbose, tagatose, glyceraldehyde,dihydroxyacetone, a monodeoxy derivative of these monosaccharides suchas rhamnose, glucuronic acid or a salt of glucuronic acid, any of whichare unprotected, partially protected (e.g., less than all hydroxylgroups are protected) or fully protected with independently selectedprotecting groups (e.g., acetoxy or propionoxy), including moieties suchβ-D-glucopyranosyl, β-D-glucopyranuronosyl,β-D-2-acetamido-2-deoxy-glucopyranosyl, β-D-galactopyranosyl,β-D-fucopyranosyl, β-L-fucopyranosyl, α-D-fructofuranosyl,β-D-fructofuranosyl, β-D-xylopyranosyl, β-L-xylopyranosyl,α-D-arabanopyranosyl, α-L-arabanopyranosyl, α-L-rhamnopyranosyl,α-D-rhamnopyranosyl, α-D-cellobiosyl, β-D-cellobiosyl, β-D-lactosyl,β-D-maltosyl, β-D-gentiobiosyl,3-O-β-D-galactopyranosyl-α-D-arabanopyranosyl or β-D-maltotriosyl, anyof which are optionally protected and where the variable group to whichthey are bonded is in the α- or β-configuration, or

an oligosaccharide, e.g., 2, 3, 4 or more linked and independentlyselected monosaccharides that comprise a D-, L- or DL-mixture ofglucose, fructose, mannose, idose, galactose, allose, gulose, altrose,talose, fucose, erythrose, threose, lyxose, erythrulose, ribulose,xylulose, ribose, arabinose, xylose, psicose, sorbose, tagatose,glyceraldehyde, N-acetylglucosamine, dihydroxyacetone or a monodeoxy ordideoxy derivative of any of these, with adjacent monosaccharides havingthe glycosidic linkage at the anomeric carbon of each monosaccharideunit independently alpha or beta linked, e.g., 1→2, 1→3, 1→4, and/or 1→6glycosidic bonds in the α- and/or β-configuration, e.g.,-glucose-mannose, -glucose-mannose-mannose, -mannose-mannose,-mannose-mannose-man nose, -glucose-galactose, -galactose-glucose,-fructose-galactose, -galactose-fructose, -galactose-galactose,-galactose-mannose, -glucuronic acid-glucose, -glucose-glucose,—(O-1β)-D-glucopyranosyl-(1α-O-4)-D-glucopyranoside,—(O-1β)-tetra-O-acetyl-D-glucopyranosyl-(1β-O-4)-tri-O-acetyl-D-glucopyranoside,—(O-1β)-D-galactopyranosyl-(1β-O-4)-D-glucopyranoside, wherein one ormore of the monosaccharides are optionally partially or fully protected,e.g., with —C(O)—CH₃ or —C(O)—C₂H₅ to protect 1, 2, 3, 4 or morehydroxyl groups, including moieties such α-D-cellobiosyl,β-D-cellobiosyl, β-D-lactosyl, β-D-maltosyl, β-D-gentiobiosyl,3-O-β-D-galactopyranosyl-α-D-arabanopyranosyl or β-D-maltotriosyl, anyof which are optionally protected and where the variable group to whichthey are bonded is in the α- or β-configuration, or

a glycol or polyethyleneglycol or a derivative, e.g., propylene glycol,ethylene glycol, 1,4-butylene glycol, 1,3-butylene glycol, 1,2-butyleneglycol, —O—C(O)—O—(CH₂CH₂O)_(n)—H, —C(O)—CH₂—O—C(O)—O—(CH₂CH₂O)_(n)—H or—O—(CH₂CH₂O)_(n)—H, where n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or

an acetal or spiro ring, e.g., —O—CH₂—O—, —O—(CH₂)₂—O—, —O—(CH₂)₃—O— or—[C(R³⁶)₂]₁₋₄—O—, —O—C(O)—CH₂—, —O—C(O)—CH₂—CH₂—, —O—C(O)—CH₂—CH₂—CH₂—,—O—C(O)—CHR¹⁰—, —O—C(O)—CHR¹⁰—CHR¹⁰—, —O—C(O)—(CHR¹⁰)₃—, —NH—(CH₂)₂—O—,—NH—(CH₂)₂—NH—, —NH—(CH₂)₂—S—, —CH₂—N═CH—NH—, —NH—(CH₂)₃—O—,—NH—(CH₂)₃—S—, —NH—(CH₂)₃—O—, where R¹⁰ are independently selected andoptionally independently are —H, —F, —Cl, —Br, —I, —CH₃, —C₂H₅, —CF₃,—C₂F₅, —CH₂CF₃, —OH, —CN, —SCN, —OCH₃ or —OC₂H₅, and where each R³⁶independently is —H, —F, —Cl, —Br, —I or an organic moiety such asC1-C10 optionally substituted alkyl (e.g., methyl or ethyl), C2-10alkenyl, aryl or a heterocycle, any of which are optionally substitutedas described herein, e.g., —CF₃ or —CH₂OH, or

thioacetal, e.g., —S—CH₂—O—, —S—(CH₂)₂—O—, —S—(CH₂)₃—O—, —S—CH₂—S—,—S—(CH₂)₂—S—, —S—(CH₂)₃—S— or —S—[C(R³⁶)₂]₁₋₄—S— where each R³⁶independently is —H, —F, —Cl, —Br, —I or an organic moiety such asC1-C10 optionally substituted alkyl (e.g., methyl or ethyl), C2-10alkenyl, aryl or a heterocycle, any of which are optionally substitutedas described herein, e.g., —CF₃ or —CH₂OH. The salts, ionized forms andsolvates of any of these moieties are also included, e.g., where a groupsuch as —NH₂ or —COOH is ionized to generate a moiety such as —NH₃ ⁺Cl⁻,—NH₃ ⁺Br⁻, —COO⁻Na⁺ or —COO⁻K⁺.

For any of these exemplary F1C, e.g., the B, C, D, E, F and Gstructures, some embodiments are characterized by the presence of one ortwo independently selected substitutions at R^(10A), R^(10B), R^(10C)and R^(10D) and optionally:

(a) R^(10E) (when present at the 5-position), R^(10F), R^(10G) andR^(10H) are independently selected R¹⁰ groups in the α,β,α,α or β,β,α,αconfigurations respectively, R¹ is an oxygen-bonded, nitrogen-bonded ora sulfur-bonded moiety such as —OH, ═O, —SH, ═NOH, —NH(C1-C8 optionallysubstituted alkyl), an ester, an ether, a thioester, or a thioether,R^(1A) is —H, absent, a carbon-bonded moiety such as an acyl moiety,optionally substituted alkyl or optionally substituted alkylaryl, R² isa halogen or an oxygen-bonded or a sulfur-bonded moiety, R^(2A) is —H,absent, a carbon-bonded moiety, R³ is a halogen or an oxygen-bonded or asulfur-bonded moiety, R^(3B) is —H, absent, a carbon-bonded moiety, R⁴is a halogen, an oxygen-bonded or a sulfur-bonded moiety, R^(4A) is —H,absent, a carbon-bonded moiety such as an acyl moiety, optionallysubstituted alkyl or optionally substituted alkylaryl,

(b) R^(10E) (if present), R^(10F), R^(10G) and R^(10H) are independentlyselected R¹⁰ groups in the α,β,α,α or β,β,α,α configurationsrespectively, R^(1A) is —H, an oxygen-bonded, nitrogen-bonded or asulfur-bonded moiety, R¹ is —H, a carbon-bonded moiety, R² is a halogenor an oxygen-bonded or a sulfur-bonded moiety, R^(2A) is —H, absent, acarbon-bonded moiety, R³ is a halogen or an oxygen-bonded or asulfur-bonded moiety, R^(3B) is —H, absent, a carbon-bonded moiety, R⁴is a halogen, an oxygen-bonded or a sulfur-bonded moiety, R^(4A) is —H,absent or a carbon-bonded moiety,

(c) R^(10E) (if present), R^(10F), R^(10G) and R^(10H) are independentlyselected R¹⁰ groups in the α,β,α,α or β,β,α,α configurationsrespectively, R¹ is an oxygen-bonded, nitrogen-bonded or a sulfur-bondedmoiety, R^(1A) is —H, absent or a carbon-bonded moiety, R² is a halogenor an oxygen-bonded or a sulfur-bonded moiety, R^(2A) is —H, absent or acarbon-bonded moiety, R³ is a halogen or an oxygen-bonded or asulfur-bonded moiety, R^(3B) is —H, absent or a carbon-bonded moiety,R^(4A) is a halogen, an oxygen-bonded or a sulfur-bonded moiety, R⁴ is—H, a halogen or a carbon-bonded moiety,

(d) R^(10E) (if present), R^(10F), R^(10G) and R^(10H) are independentlyselected R¹⁰ groups in the α,β,α,α or β,β,α,α configurationsrespectively, R¹ is an oxygen-bonded, nitrogen-bonded or a sulfur-bondedmoiety, R^(1A) is —H, absent, a carbon-bonded moiety, R² is a halogen oran oxygen-bonded or a sulfur-bonded moiety, R^(2A) is —H, absent or acarbon-bonded moiety, R³ is a halogen or an oxygen-bonded or asulfur-bonded moiety, R^(3B) is —H, absent or a carbon-bonded moiety, R⁴is a halogen, an oxygen-bonded or a sulfur-bonded moiety, R^(4A) is —H,absent or a carbon-bonded moiety,

(e) R^(10E) (if present), R^(10F), R^(10G) and R^(10H) are independentlyselected R¹⁰ groups in the α,β,α,α or β,β,α,α configurationsrespectively, R¹ is an oxygen-bonded, nitrogen-bonded or a sulfur-bondedmoiety, R^(1A) is —H, absent or a carbon-bonded moiety, R² is a halogenor an oxygen-bonded or a sulfur-bonded moiety, R^(2A) is —H, absent or acarbon-bonded moiety, R^(3B) is a halogen or an oxygen-bonded or asulfur-bonded moiety, R³ is —H, a carbon-bonded moiety, R⁴ is a halogen,an oxygen-bonded or a sulfur-bonded moiety, R^(4A) is —H, absent or acarbon-bonded moiety,

(f) R^(10E) (if present), R^(10F), R^(10G) and R^(10H) are independentlyselected R¹⁰ groups in the α,β,α,α or β,β,α,α configurationsrespectively, R^(1A) is —H, an oxygen-bonded, nitrogen-bonded or asulfur-bonded moiety, R¹ is —H, a carbon-bonded moiety, R² is a halogenor an oxygen-bonded or a sulfur-bonded moiety, R^(2A) is —H, absent or acarbon-bonded moiety, R³ is a halogen or an oxygen-bonded or asulfur-bonded moiety, R^(3B) is —H, absent or a carbon-bonded moiety,R^(4A) is a halogen, an oxygen-bonded or a sulfur-bonded moiety, R⁴ is—H, a carbon-bonded moiety, or

(g) R^(10E) (if present), R^(10F), R^(10G) and R^(10H) are independentlyselected R¹⁰ groups in the α,β,α,α or β,β,α,α configurationsrespectively, R¹ is a halogen or an oxygen-bonded, nitrogen-bonded,carbon bonded or a sulfur-bonded moiety, R^(1A) is —H, a carbon-bondedor nitrogen-bonded moiety and R², R^(2A), R³ R^(3B), R⁴ and R^(4A) areas described any of in the foregoing embodiments or elsewhere herein. Inany of these embodiments, R⁵-R⁹ are independently selected moieties asdescribed herein and the oxygen-bonded, nitrogen-bonded, carbon bondedor sulfur-bonded moieties at R¹, R^(1A), R², R^(2A), R³, R^(3B), R⁴, andR^(4A) include atoms or groups described herein. These embodimentscontain formula B, C, D, E, F and G compounds wherein one or two of R¹,R^(1A), R², R^(2A), R³, R^(3B), R⁴, and R^(4A) are independentlyselected nitrogen-bonded moieties, one, two or three of R¹, R^(1A), R²,R^(2A), R³, R^(3B), R⁴, and R^(4A) are independently selectedcarbon-bonded moieties and one, two, three, four or five of R², R^(2A),R³, R^(3B), R⁴, and R^(4A) are independently selected or halogen atomsor oxygen-bonded or sulfur-bonded moieties.

These embodiments contain F1C, such as the B, C, D, E, F and Gstructures wherein R⁴ and R^(4A) are present, i.e., no 16-17 double bondis present, and both are the same, such as optionally substituted alkyl,halogen, ether, ester, thioether, thioester, e.g., —OR^(PR), —SR^(PR),—F, —Cl, —Br, —I, methyl, ethyl, methoxy, ethoxy acetate or propionate.However, in many embodiments, when they are both present, R⁴ and R^(4A)are two independently selected dissimilar moieties defined herein, e.g.,independently selected —H, —OH, —OR^(PR), an ester (e.g., —OC(O)—CH₃,—OC(O)—C₂H₅, —OC(O)—C3 alkyl, —OC(O)—C4 alkyl,), ether (e.g., —OCH₃,—OC₂H₅, —OCH₂CH₂CH₃, or —OCH(CH₃)CH₃, —O—C4 alkyl, —O—C5 alkyl or —O—C6alkyl), a thioester, a thioether, an acyl moiety, a carbonate, acarbamate an amide, a monosaccharide, a disaccharide, or an amino acid,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl or another moiety described herein.

For any F1C, examples of dissimilar R⁴ and R^(4A) moieties at the17-position include (α-ester, β-optionally substituted alkynyl),(β-ester, α-optionally substituted alkynyl), (α-thioester, β-optionallysubstituted alkynyl), (β-thioester, α-optionally substituted alkynyl),(α-ester, β-optionally substituted alkenyl), (β-ester, α-optionallysubstituted alkenyl), (α-thioester, β-optionally substituted alkenyl),(β-thioester, α-optionally substituted alkenyl), (α-optionallysubstituted alkyl, β-ester), (β-optionally substituted alkyl, α-ester),(α-optionally substituted alkyl, β-optionally substituted amine),(β-optionally substituted alkyl, α-optionally substituted amine),(α-optionally substituted alkyl, β-halogen)-, (β-optionally substitutedalkyl, α-halogen), (α-halogen, β-ether), (β-halogen, α-ether),(α-halogen, β-optionally substituted alkyl), (β-halogen, α-optionallysubstituted alkyl), (β-ester, α-acyl), (α-ester, β-acyl), (β-ester,α-C(O)—C1-C10 optionally substituted alkyl), (α-ester, β-C(O)—C1-C10optionally substituted alkyl), (H-thioester, α-C(O)—C1-C10 optionallysubstituted alkyl), (α-thioester, β-C(O)—C1-C10 optionally substitutedalkyl), (β-OH, α-ester), (α-OH, β-ester), (β-OH, α-ether), (α-OH,β-ether), (β-OH, α-acyl), (α-OH, β-acyl), (α-halogen, β-OR^(PR)),(β-halogen, α-OR^(PR)), (α-F, β-ester), (β-F, α-ester), (α-F, β-ether),(β-F, α-ether), (α-Br, β-ether), (β-Br, α-ether), (α-F, β-optionallysubstituted alkyl), (β-F, α-optionally substituted alkyl), (α-OH,β-optionally substituted alkynyl), (β-OH, α-optionally substitutedalkynyl), (α-OH, β-C≡CCH₂-halogen), (β-OH, α-C≡CCH₂-halogen), (α-OH,β-C≡C-halogen), (β-OH, α-C≡C-halogen), (β-epoxy, α-halogen, where theepoxy is formed with an adjacent steroid nucleus atom), (α-epoxy,β-halogen), (α-cyclopropyl, β-halogen), (β-cyclopropyl, α-halogen),(α-cyclopropyl, β-optionally substituted alkyl), (β-cyclopropyl,α-optionally substituted alkyl), (α-optionally substituted alkyl,β-NH—C1-C8 optionally substituted alkyl), (β-optionally substitutedalkyl, α-NH—C1-C8 optionally substituted alkyl), (α-ether, β-NH—C1-C8optionally substituted alkyl), (β-ether, α-NH—C1-C8 optionallysubstituted alkyl), (α-thioester, β-NH—C1-C8 optionally substitutedalkyl), (β-thioester, α-NH—C1-C8 optionally substituted alkyl),(α-ester, β-NH—C1-C8 optionally substituted alkyl), (β-ester, α-NH—C1-C8optionally substituted alkyl), (α-C(O)CH₃, β-NH—C1-C8 optionallysubstituted alkyl), (β-C(O)CH₃, α—NH—C1-C8 optionally substitutedalkyl), (α-OH, β-NH—C1-C8 optionally substituted alkyl), (β-OH,α-NH—C1-C8 optionally substituted alkyl) and other combinations ofgroups that are within the scope of R⁴ and R^(4A). Such moieties, whichare the same or different can also be at 1, 2, 3 or more R¹ and R^(1A),R² and R^(2A), R³ and R^(3B) variable groups, and/or the R¹⁰ variablegroups at R⁷, R³ and R⁹.

Specific dissimilar R⁴ and R^(4A) moieties include, e.g., (α-F, β-CH₃),(β-F, α-CH₃), (α-F, β-C₂H₅), (β-F, α-C₂H₅), (α-Br, β-OCH₃), (β-Br,α-OCH₃), (α-F, β-OCH₃), (β-F, α-OCH₃), (α-F, β-OH), (β-F, α-OH), (α-Br,β-OCH₃), (β-Br, α-OCH₃), (α-F, β-CH₃), (β-F, α-CH₃), (α-Br, β-CH₃),(β-Br, α-CH₃), (α-OH, β-CCCH₃), (β-OH, α-CCCH₃), (α-OH, β-CCCH₂OH),(β-OH, α-CCCH₂OH), (α-OH, β-CCH), (β-OH, α-CCH), (α-CH₃, β-OC(O)CH₃),(β-CH₃, α-OC(O)CH₃), (α-C₂H₅, β-OC(O)CH₃), (β-C₂H₅, (α-OC(O)CH₃),(α-C₃H₇, β-OC(O)CH₃), (β-C₃H₇, α-OC(O)CH₃), (α-C₄H₉, β-OC(O)CH₃),(β-C₄H₉, α-OC(O)CH₃), (α-C₂H₃, β-OC(O)CH₃), (β-C₂H₃, α-OC(O)CH₃),(α-C₂H₄OH, β-OC(O)CH₃), (β-C₂H₄OH, α-OC(O)CH₃), (α-C₃H₅, β-OC(O)CH₃),(β-C₃H₅, (α-OC(O)CH₃), (α-C₄H₇, β-OC(O)CH₃), (β-C₄H₇, α-OC(O)CH₃),(α-C₃H₃, β-OC(O)CH₃), (β-C₃H₃, (α-OC(O)CH₃), (α-C₄H₅, β-OC(O)CH₃),(β-C₄H₅, (β-OC(O)CH₃), (α-CH₃, β-OC(O)C₂H₅), (β-CH₃, α-OC(O)C₂H₅),(α-C₂H₅, β-OC(O)C₂H₅), (β-C₂H₅, α-OC(O)C₂H₅), (α-C₃H₇, β-OC(O)C₂H₅),(β-C₃H₇, α-OC(O)C₂H₅), (α-C₄H₉, β-OC(O)C₂H₅), (β-C₄H₉, α-OC(O)C₂H₅),(β-C₂H₃, β-OC(O)C₂H₅), (β-C₂H₃, α-OC(O)C₂H₅), (α-C₂H₄OH, β-OC(O)C₂H₅),(β-C₂H₄OH, α-OC(O)C₂H₅), (α-C₃H₅, β-OC(O)C₂H₅), (β-C₃H₅, α-OC(O)C₂H₅),(α-C₄H₇, β-OC(O)C₂H₅), (β-C₄H₇, α-OC(O)C₂H₅), (α-C₃H₃, β-OC(O)C₂H₅),(β-C₃H₃, α-OC(O)C₂H₅), (α-C₄H₅, β-OC(O)C₂H₅), (β-C₄H₅, α-OC(O)C₂H₅),(α-C(O)CH₃, β-OC(O)CH₃), (β-C(O)CH₃, α-OC(O)CH₃), (α-C(O)C₂H₅,β-OC(O)CH₃), (β-C(O)C₂H₅, α-OC(O)CH₃), (α-CH₃, β-SC(O)CH₃), (β-CH₃,α-SC(O)CH₃), (α-C₂H₅, β-SC(O)CH₃), (β-C₂H₅, α-SC(O)CH₃), (α-C₃H₇,P—SC(O)CH₃), (β-C₃H₇, α-SC(O)CH₃), (α-C₄H₉, β-SC(O)CH₃), (β-C₄H₉,α-SC(O)CH₃), (α-C₂H₃, β-SC(O)CH₃), (β-C₂H₃, α-SC(O)CH₃), (α-C₂H₄OH,β-SC(O)CH₃), (β-C₂H₄OH, α-SC(O)CH₃), (α-C₃H₅, β-SC(O)CH₃), (β-C₃H₅,α-SC(O)CH₃), (α-C₄H₇, β-SC(O)CH₃), (β-C₄H₇, α-SC(O)CH₃), (α-C₃H₃,β-SC(O)CH₃), (β-C₃H₃, α-SC(O)CH₃), (α-C₄H₅, β-SC(O)CH₃), (β-C₄H₅,α-SC(O)CH₃), (α-CH₃, β-SC(O)C₂H₅), (β-CH₃, α-SC(O)C₂H₅), (α-C₂H₅,β-SC(O)C₂H₅), (β-C₂H₅, α-SC(O)C₂H₅), (α-C₃H₇, β-SC(O)C₂H₅), (β-C₃H₇,α-SC(O)C₂H₅), (α-C₄H₉, β-SC(O)C₂H₅), (β-C₄H₉, α-SC(O)C₂H₅), (α-C₂H₃,β-SC(O)C₂H₅), (β-C₂H₃, α-SC(O)C₂H₅), (α-C₂H₄OH, β-SC(O)C₂H₅), (β-C₂H₄OH,α-SC(O)C₂H₅), (α-C₃H₅, β-SC(O)C₂H₅), (β-C₃H₅, α-SC(O)C₂H₅), (α-C₄H₇,β-SC(O)C₂H₅), (β-C₄H₇, α-SC(O)C₂H₅), (α-C₃H₃, β-SC(O)C₂H₅), (β-C₃H₃,(α-SC(O)C₂H₅), (α-C₄H₅, β-SC(O)C₂H₅), (β-C₄H₅, α-SC(O)C₂H₅), (α-C(O)CH₃,β-SC(O)CH₃), (β-C(O)CH₃, α-SC(O)CH₃), (α-C(O)C₂H₅, β-SC(O)CH₃),(β-C(O)C₂H₅, α-SC(O)CH₃), (α-C(O)CH₃, β-NH—CH₃), (β-C(O)CH₃, α-NH—CH₃),(α-OH, β-NH—CH₃), (β-OH, α-NH—CH₃), (α-C(O)CH₃, β-N(CH₃)₂), (β-C(O)CH₃,α-N(CH₃)₂), (α-OH, β-N(CH₃)₂), (β-OH, α-N(CH₃)₂), (α-C(O)CH₃,β-N(C₂H₅)₂), (β-C(O)CH₃, α-N(C₂H₅)₂), (α-OH, β-N(C₂H₅)₂), (β-OH,α-N(C₂H₅)₂), (β-epoxy, α-H), (α-epoxy, β-H), (β-epoxy, α-Br), (α-epoxy,β-Br), (β-epoxy, α-F), (α-epoxy, β-F), (β-cyclopropyl, α-H),(α-cyclopropyl, β-H), (β-cyclopropyl, α-F) and (α-cyclopropyl, β-F). Formoieties that contain an epoxy, cyclopropyl or other cyclic moiety, thecyclic moiety can be formed with an adjacent variable group, e.g., R³ orR^(3B). As is apparent from the foregoing disclosure, these or otherdissimilar moieties can also be present at one or more of, e.g., the 2-,3-, 7-, 11-, 15- or 16-positions.

Additional embodiments of the F1Cs include any F1Cs or any 2, 5, 6, 7,8, 9, 10, B, C, D, E, F or G structures, e.g., any of the F1Cs or F1Cgenera disclosed herein, wherein one or both of R⁵ or R⁶ independentlyare —H, —CH₂SH, —CHO, —CH₂NR^(PR), —CH₂NH₂, —C₄H₉, —C₃H₇, —C₂H₅, —CH₃,—C₂H₄OH, —C₂H₄SH, —C₂H₄NH₂, —CH₂CHO, —CH₂CH₂NR^(PR), —CH₂CH₂OH,—CH₂CH₂SH, —CH₂CH₂C₆H₅, —CH₂C₆H₅, —C₆H₅ or optionally substituted alkylwherein any phenyl (C₆H₅) moiety in the foregoing groups is optionallysubstituted at the phenyl ring with 1, 2, 3, 4 or 5 moietiesindependently selected from those described for esters herein andincluding C1-C6 alkyl (optionally substituted with 1 or 2 independentlyselected —OH, —SH, —O—, —S— or —NH—) C1-C6 alkoxy, —F, —Cl, —Br, —I,—CN, —NO₂, —OH, —SH, —COOR^(PR), —NHR^(PR) and —C(O)—C1-C6 alkyl.Typically R⁵ or R⁶ are both in the β-configuration, but they may be in,e.g., the α,β or β,α configurations respectively.

In some embodiments, one or more of the variable groups that are bondedto the F1C, e.g., R¹-R⁵, R¹⁰, R^(10A), R^(10B), R^(10C), R^(10D), R¹⁵,R¹⁷ and R¹³, independently are —H, —OH, ═O, —SH, ═S, —SCN, —CN, —NO₂,—NH₂, —N₃, —F, —Cl, —Br, —I, epoxide, —CHO, —CHS, ═CH₂, ═CH—CH₃,═CH—CH₂OH, ═CH—CH₂—CH₃, ═CH—CH(OH)—CH₃, ═CH—C(O)—CH₃,═CH—CH(halogen)-CH₃, —CH₂(halogen), —CH(halogen)-CH₃,—CH₂—CH(halogen)-CH₃, —CH₂—(CH₂)_(n)—NH₂,—CH₂—(CH₂)_(n)—N—H[(CH₂)_(n)—CH₃], —CH(CH₃)—NH—(CH₂)_(m)—NH₂,—CH(CH₃)—NH—(CH₂)_(m)—N—H[(CH₂)_(n)—CH₃],—CH(CH₃)—NH—(CH₂)_(m)—NH(optionally substituted alkyl),—CH(CH₃)—NH—(CH₂)_(m)—N(optionally substituted alkyl)₂,—CH(CH₃)—NH—(CH₂)₂₋₃—N(CH₃)₂, ═NOH, ═NOC(O)CH₃, ═NOCH₃, ═NO—CH₂CH₃,—C(O)—CH₃, —C(O)—(CH₂)₁₋₄—CH₃, —CCH, —CCCH₃, —CH═CH₂, —CH═CH₂CH₃,—O—C(O)—(CH₂)_(m)—(CF₂)_(n)—CH₃, —O—C(O)—(CH₂)_(m)—(CF₂)_(n)—CF₃,—O—C(O)—(CH₂)_(m)—(CF₂)_(n)—CH₂F, —O—C(O)—O—(CH₂)_(m)—(CF₂)_(n)—CH₃,—O—C(O)—O—(CH₂)_(m)—(CF₂)_(n)—CF₃, —O—C(O)—O—(CH₂)_(m)—(CF₂)_(n)—CH₂F,—O—C(O)—NH—(CH₂)_(m)—(CF₂)_(n)—CH₃, —O—C(O)—NH—(CH₂)_(m)—(CF₂)_(n)—CF₃,—O—C(O)—NH—(CH₂)_(m)—(CF₂)_(n)—CH₂F (where m is 1, 2, 3, 4, 5, 6, 7, 8,9 or 10, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and p is 0, 1 or 2),—CH(CH₃)—(CH₂)₂—C(O)NH—CH₂COOH, —CH(CH₃)—(CH₂)₂—C(O)NH—CH₂SO₃H,—OSi(CH₃)₂C(CH₃)₃, —C(OH)═CHCH₃, ═CH(CH₂)₀₋₁₅CH₃, —(CH₂)₀₋₁₄—CH₂F,—(CH₂)₀₋₁₄—CH₂Cl, —(CH₂)₀₋₁₄—CH₂Br, —(CH₂)₀₋₁₄—CH₂I,—(CH₂)₂₋₁₀—O—(CH₂)₀₋₄—CH₃, —(CH₂)₂₋₁₀—S—(CH₂)₀₋₄—CH₃,—(CH₂)₂₋₁₀—NH—(CH₂)₀₋₄—CH₃, —O—(CH₂)₀₋₁₄—CH₂F, —O—(CH₂)₀₋₁₄—CH₂Cl,—O—(CH₂)₀₋₁₄—CH₂Br, —O—(CH₂)₀₋₁₄—CH₂I, —O—(CH₂)₂₋₁₀—O—(CH₂)₀₋₄—CH₃,—O—(CH₂)₂₋₁₀—S—(CH₂)₀₋₄—CH₃, —O—(CH₂)₂₋₁₀—NH—(CH₂)₀₋₄—CH₃,—O—C(O)—(CH₂)₀₋₁₄—CH₂F, —O—C(O)—(CH₂)₀₋₁₄—CH₂Cl,—O—C(O)—(CH₂)₀₋₁₄—CH₂Br, —O—C(O)—(CH₂)₀₋₁₄—CH₂I,—O—C(O)—(CH₂)₂₋₁₀—O—(CH₂)₀₋₄—CH₃, —O—C(O)—(CH₂)₂₋₁₀—S—(CH₂)₀₋₄—CH₃,—O—C(O)—(CH₂)₂₋₁₀—NH—(CH₂)₀₋₄—CH₃, —O—C(S)—(CH₂)₀₋₁₄—CH₂F,—O—C(S)—(CH₂)₀₋₁₄—CH₂Cl, —O—C(S)—(CH₂)₀₋₁₄—CH₂Br,—O—C(S)—(CH₂)₀₋₁₄—CH₂I, —O—C(S)—(CH₂)₂₋₁₀—O—(CH₂)₀₋₄—CH₃,—O—C(S)—(CH₂)₂₋₁₀—S—(CH₂)₀₋₄—CH₃, —O—C(S)—(CH₂)₂₋₁₀—NH—(CH₂)₀₋₄—CH₃,—(CH₂)₀₋₁₆NH₂, —(CH₂)₀₋₁₅CH₃, —(CH₂)₀₋₁₅CN, —(CH₂)₀₋₁₅CH═CH₂,—(CH₂)₀₋₁₅NHCH(O), —(CH₂)₀₋₁₆NH—(CH₂)₀₋₁₅CH₃, —(CH₂)₀₋₁₅CCH,—(CH₂)₀₋₁₅OC(O)CH₃, —(CH₂)₀₋₁₅OCH(OH)CH₃, —(CH₂)₀₋₁₅C(O)OCH₃,—(CH₂)₀₋₁₅C(O)OCH₂CH₃, —(CH₂)₀₋₁₅C(O)(CH₂)₀₋₁₅CH₃,—(CH₂)₀₋₁₅C(O)(CH₂)₀₋₁₅CH₂OH, —O(CH₂)₁₋₁₆NH₂, —O(CH₂)₁₋₁₅CH₃,—O(CH₂)₁₋₁₅CN, —O(CH₂)₁₋₁₅CH═CH₂, —O(CH₂)₁₋₁₅NHCH(O),—O(CH₂)₁₋₁₆NH—(CH₂)₁₋₁₅CH₃, —O(CH₂)₁₋₁₅CCH, —O(CH₂)₁₋₁₅OC(O)CH₃,—O(CH₂)₁₋₁₅OCH(OH)CH₃, —O(CH₂)₁₋₁₅C(O)OCH₃, —O(CH₂)₁₋₁₅C(O)OCH₂CH₃,—O(CH₂)₁₋₁₅C(O)(CH₂)₀₋₁₅CH₃, —O(CH₂)₁₋₁₅C(O)(CH₂)₀₋₁₅CH₂OH,—OC(O)(CH₂)₁₋₁₆NH₂, —OC(O)(CH₂)₁₋₁₅CH₃, —C(O)O(CH₂)₁₋₁₅CN,—C(O)O(CH₂)₁₋₁₅CH═CH₂, —OC(O)(CH₂)₁₋₁₅NHCH(O),—OC(O)(CH₂)₁₋₁₆NH—(CH₂)₁₋₁₅CH₃, —OC(O)(CH₂)₁₋₁₅CCH,—OC(O)(CH₂)₁₋₁₅OC(O)CH₃, —OC(O)(CH₂)₁₋₁₅OCH(OH)CH₃,—OC(O)(CH₂)₁₋₁₅C(O)OCH₃, —OC(O)(CH₂)₁₋₁₅C(O)OCH₂CH₃,—OC(O)(CH₂)₁₋₁₅C(O)(CH₂)₀₋₁₅CH₃, —OC(O)(CH₂)₁₋₁₅C(O)(CH₂)₀₋₁₅CH₂OH,—C(O)—(CH₂)_(0, 1, 2, 3, 4, 5, 6)—OPO₃HR^(PR),—C(O)—(CH₂)_(0, 1, 2, 3, 4, 5, 6)—C(O)—C1-C4 optionally substitutedalkyl, —O-cyclopentyl,—O—(CH₂)_(0, 1, 2, 3, 4)—C(O)—CH═CH—CH—(CH₂)_(0, 1, 2, 3, 4)—CH₃,—C(O)-optionally substituted phenyl, —C(O)-disubstituted phenyl,—C(O)-p-substituted phenyl, —C(O)-o-substituted phenyl,—CH(CH₃)—(CH₂)_(1, 2, 3, 4)—C(═CH₂)—CH(CH₃)₂,—CH(CH₃)—(CH₂)_(1, 2, 3, 4)—CH(CH₃)₂,—C(CH₃)═N—(CH₂)_(1, 2, 3, 4)—CH₂OH,—C(O)—(CH₂)_(0, 1, 2, 3, 4, 5, 6)—O—C(O)—(CH₂)_(1, 2, 3, 4, 5, 6)—C(O)—O—C1-C4optionally substituted alkyl,—C(O)—(CH₂)_(0, 1, 2, 3, 4, 5, 6)—O—C(O)—(CH₂)_(1, 2, 3, 4, 5, 6)—C(O)—OR^(PR),—C≡C-cyclopropyl, —CH═CH-cyclopropyl, —C≡C—C(═CH₂)—CH₃, —C≡C—C(═CH₂)—F,—C≡C—C(═CH₂)—Cl, —C≡C—C(═CH₂)—Br, —C≡C—C(═CH₂)—F, —C≡C—C(═CH₂)—Cl,—C≡C—C(═CH₂)—Br, —O—C(O)—CF₃, —O—C(O)-cyclopropyl, —O—C(O)-cyclobutyl,—O—C(O)—CH₂—O—C(O)—CH═CH—COOR^(PR), —O—C(O)—CH(C₂H₅)(C₄H₉),—O—C(O)—CH(C₂H₅)₂, —O—C(O)—CH(C₄H₉)₂,—O—C(O)—(CH₂)_(1, 2, 3, 4, 5, 6)—CH₃,═CH—O—(CH₂)_(1, 2, 3, 4, 5, 6)—CH₃, —CH═CH₂,—CH(OH)—(CH₂)_(0, 1, 2, 3, 4)—H, —C(CH₃)(OH)—(CH₂)_(0, 1, 2, 3, 4)—H,—O—(C(O)— (CH₂)_(0, 1, 2, 3, 4)—CH₃, —O—(C(O)—(CH₂)_(0, 1, 2, 3, 4)—CF₃, —C(O)—CH₂—O—C(O)—CH₂CH₂—C(O)OR^(PR)

C1-C10 optionally substituted alkyl, heterocycle, aryl,phosphoenolpyruvate, D-glucosamine, glucholic acid, glucuronic acid,pantothenic acid, pyruvic acid, glucose, fructose, mannose, sucrose,lactose, fucose, rhamnose, galactose, ribose,(O-1)-D-galactopyranosyl-(1-O-4)-D-glucopyranoside,(O-1)-tetra-O-acetyl-D-glucopyranosyl-(1-O-4)-tri-O-acetyl-D-glucopyranoside,2′-deoxyribose, 3′-deoxyribose, glycerol, 3-phosphoglycerate, a PEG (PEG20, PEG 100, PEG 200, PEG 10000), a polyoxyalkylene polymer, glycine,alanine, phenylalanine, threonine, proline, 4-hydroxyproline or anoligonucleotide or analog that comprises about 4 to about 21 monomers,where R^(PR) independently are —H or a protecting group. In someembodiments, one, two or three of R¹, R² and R⁴ independently are one ofthese moieties and other variable groups in the F1C are as otherwisedefined herein. In other embodiments, one or two of R^(10A), R^(10B),R^(10C), R^(10D), are not —H, and 1, 2, 3 or 4 of (1) R¹, R³ and R⁴, (2)R¹, R² and R⁴, (3) R¹, R³, R⁴ and R⁹, (4) R¹, R³, R⁴ and R⁸, (5) R¹, R³,R⁴ and R⁹, (6) R¹, R², R³ and R⁴, (7) R¹, R², R³, R⁴ and R⁷ (8) R¹, R²,R³, R⁴ and R⁸ or (9) R¹, R², R³, R⁴ and R⁹, independently are one ofthese moieties, e.g., any substituent except —H, —CH₂— or ═CH—, whileother variable groups, e.g., R⁵ and R⁶, are as otherwise defined herein.

F1C embodiments also include compounds where 1, 2 or more of, e.g., R¹,R², R³, R⁴ and R¹⁰ are a lipid moiety such as a fatty acid, amonoacylglyceride, a diacylglyceride, a phospholipid, a glycolipid, asphingolipid or a glycerophospholipid that is esterified, linked throughan ether (—O—) or acyl moiety or otherwise bonded to the F1C. Exemplaryfatty acid esters include —C(O)—(CH₂)_(m)—H where m is 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 15, 17, 19 or 21 and —C(O)—(CH₂)_(n)—CH═CH—(CH₂)_(n)—Hwhere each n independently is 1, 2, 3, 4, 5, 6, 7 or 8. Other lipidmoieties that can be bonded to the steroid include phosphatidic acid,phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine andphosphatidylglycerol. The lipid moiety may be bonded to the steroidthrough a hydroxyl or oxygen, phosphate, sulfate or amine at a variablegroup. Such lipid moieties may be bonded to any of the F1Cs or genera ofF1Cs disclosed herein.

Specific F1Cs that can be used in the clinical treatments and othermethods described herein include the following groups of compounds.

Group 1. Exemplary embodiments include the formula 1 compounds namedaccording to the compound structure designations given in Tables A and Bbelow. Each compound named in Table B is depicted as a compound havingformula B

where R⁵ and R⁶ are both —CH₃, there is no double bond at the 1-2-,4-5-, 5-6 or 16-17 positions, R⁷, R⁸ and R⁹ are all —CH₂—, R^(10A),R^(10B), R^(10C), R^(10D), R^(10E), R^(10F), R^(10G) and R^(10H) are all—H and R¹, R², R³ and R⁴ are the substituents designated in Table A. Thecompounds named according to Tables A and B are referred to as “group 1”compounds.

Compounds named in Table B are named by numbers assigned to R¹, R², R³and R⁴ according to the following compound naming convention,R¹.R².R³.R⁴, using the numbered chemical substituents in Table A. EachTable A number specifies a different structure for each of R¹, R², R³and R⁴. When R¹, R², R³ or R⁴ is a divalent moiety, e.g., ═O, thehydrogen at the corresponding position is absent. Thus, the group 1compound named 1.2.1.1 is a formula B structure with a β-hydroxyl bondedto carbons at the 3- and 7-positions (the variable groups R¹ and R²respectively), an α-bromine bonded to carbon 16 (the variable group R³)and double bonded oxygen (═O) at carbon 17 (the variable group R⁴),i.e., 1.2.4.1 is 3β,7β-dihydroxy-16α-fluoro-17β-aminoandrostane and hasthe structure

Similarly, group 1 compound 1.2.7.1 is3β,7β-dihydroxy-16-oxo-17β-aminoandrostane and compound 1.1.4.1 is3-hydroxy-16α-fluoro-17β-aminoandrostane. Exemplary compounds include3β,17β-dihydroxy-5α-androstane,3β,17β-dihydroxy-7β-methyl-5α-androstane,3β,17β-dihydroxy-7β-methoxy-5α-androstane,3β,7β,17β-trihydroxy-5α-androstane, 3β-amino-17β-hydroxy-5α-androstane3β-amino-7β,17β-dihydroxy-5α-androstane,3β-hydroxy-17β-amino-5α-androstane,3β,7β-dihydroxy-17β-amino-5α-androstane and 16α-hydroxy, 16-methylene(═CH₂), 16-oxo and 16α-halo analogs of any of these compounds.

TABLE A R¹ R² 1 —OH 1 —H 2 ═O 2 —OH 3 —SH 3 ═O 4 —NH—C(O)—OCH₃ 4 —CH₃ 5—NH₂ 5 —OCH₃ 6 —NH—C(O)—CH₃ 6 —NH₂ 7 —H 7 —NH—C(O)—CH₃ 8 —CH₃ 8 —NH—CH₃9 —O-D-β-glucoside 9 —N(CH₃)₂ 10  —O—S(O)(O)—O⁻Na⁺ 10 —NH—CH₂—COOH R³ R⁴1 —Br 1 —NH₂ 2 —Cl 2 —NH—C(O)—CH₃ 3 —I 3 —NH—C(O)—OCH₃ 4 —F 4 —NH—CH₃ 5—H 5 —N(CH₃)₂ 6 —OH 6 —N⁺(CH₃)₃ 7 ═O 7 —NH—C₂H₅ 8 —NH₂ 8 —NHOH 9—NH—C(O)—CH₃ 9 —OH 10  —NHCH₃ 10 ═O

TABLE B 1.1.1.1, 1.1.1.2, 1.1.1.3, 1.1.1.4, 1.1.1.5, 1.1.1.6, 1.1.1.7,1.1.1.8, 1.1.1.9, 1.1.1.10, 1.1.2.1, 1.1.2.2, 1.1.2.3, 1.1.2.4, 1.1.2.5,1.1.2.6, 1.1.2.7, 1.1.2.8, 1.1.2.9, 1.1.2.10, 1.1.3.1, 1.1.3.2, 1.1.3.3,1.1.3.4, 1.1.3.5, 1.1.3.6, 1.1.3.7, 1.1.3.8, 1.1.3.9, 1.1.3.10, 1.1.4.1,1.1.4.2, 1.1.4.3, 1.1.4.4, 1.1.4.5, 1.1.4.6, 1.1.4.7, 1.1.4.8, 1.1.4.9,1.1.4.10, 1.1.5.1, 1.1.5.2, 1.1.5.3, 1.1.5.4, 1.1.5.5, 1.1.5.6, 1.1.5.7,1.1.5.8, 1.1.5.9, 1.1.5.10, 1.1.6.1, 1.1.6.2, 1.1.6.3, 1.1.6.4, 1.1.6.5,1.1.6.6, 1.1.6.7, 1.1.6.8, 1.1.6.9, 1.1.6.10, 1.1.7.1, 1.1.7.2, 1.1.7.3,1.1.7.4, 1.1.7.5, 1.1.7.6, 1.1.7.7, 1.1.7.8, 1.1.7.9, 1.1.7.10, 1.1.8.1,1.1.8.2, 1.1.8.3, 1.1.8.4, 1.1.8.5, 1.1.8.6, 1.1.8.7, 1.1.8.8, 1.1.8.9,1.1.8.10, 1.1.9.1, 1.1.9.2, 1.1.9.3, 1.1.9.4, 1.1.9.5, 1.1.9.6, 1.1.9.7,1.1.9.8, 1.1.9.9, 1.1.9.10, 1.1.10.1, 1.1.10.2, 1.1.10.3, 1.1.10.4,1.1.10.5, 1.1.10.6, 1.1.10.7, 1.1.10.8, 1.1.10.9, 1.1.10.10, 1.2.1.1,1.2.1.2, 1.2.1.3, 1.2.1.4, 1.2.1.5, 1.2.1.6, 1.2.1.7, 1.2.1.8, 1.2.1.9,1.2.1.10, 1.2.2.1, 1.2.2.2, 1.2.2.3, 1.2.2.4, 1.2.2.5, 1.2.2.6, 1.2.2.7,1.2.2.8, 1.2.2.9, 1.2.2.10, 1.2.3.1, 1.2.3.2, 1.2.3.3, 1.2.3.4, 1.2.3.5,1.2.3.6, 1.2.3.7, 1.2.3.8, 1.2.3.9, 1.2.3.10, 1.2.4.1, 1.2.4.2, 1.2.4.3,1.2.4.4, 1.2.4.5, 1.2.4.6, 1.2.4.7, 1.2.4.8, 1.2.4.9, 1.2.4.10, 1.2.5.1,1.2.5.2, 1.2.5.3, 1.2.5.4, 1.2.5.5, 1.2.5.6, 1.2.5.7, 1.2.5.8, 1.2.5.9,1.2.5.10, 1.2.6.1, 1.2.6.2, 1.2.6.3, 1.2.6.4, 1.2.6.5, 1.2.6.6, 1.2.6.7,1.2.6.8, 1.2.6.9, 1.2.6.10, 1.2.7.1, 1.2.7.2, 1.2.7.3, 1.2.7.4, 1.2.7.5,1.2.7.6, 1.2.7.7, 1.2.7.8, 1.2.7.9, 1.2.7.10, 1.2.8.1, 1.2.8.2, 1.2.8.3,1.2.8.4, 1.2.8.5, 1.2.8.6, 1.2.8.7, 1.2.8.8, 1.2.8.9, 1.2.8.10, 1.2.9.1,1.2.9.2, 1.2.9.3, 1.2.9.4, 1.2.9.5, 1.2.9.6, 1.2.9.7, 1.2.9.8, 1.2.9.9,1.2.9.10, 1.2.10.1, 1.2.10.2, 1.2.10.3, 1.2.10.4, 1.2.10.5, 1.2.10.6,1.2.10.7, 1.2.10.8, 1.2.10.9, 1.2.10.10, 1.3.1.1, 1.3.1.2, 1.3.1.3,1.3.1.4, 1.3.1.5, 1.3.1.6, 1.3.1.7, 1.3.1.8, 1.3.1.9, 1.3.1.10, 1.3.2.1,1.3.2.2, 1.3.2.3, 1.3.2.4, 1.3.2.5, 1.3.2.6, 1.3.2.7, 1.3.2.8, 1.3.2.9,1.3.2.10, 1.3.3.1, 1.3.3.2, 1.3.3.3, 1.3.3.4, 1.3.3.5, 1.3.3.6, 1.3.3.7,1.3.3.8, 1.3.3.9, 1.3.3.10, 1.3.4.1, 1.3.4.2, 1.3.4.3, 1.3.4.4, 1.3.4.5,1.3.4.6, 1.3.4.7, 1.3.4.8, 1.3.4.9, 1.3.4.10, 1.3.5.1, 1.3.5.2, 1.3.5.3,1.3.5.4, 1.3.5.5, 1.3.5.6, 1.3.5.7, 1.3.5.8, 1.3.5.9, 1.3.5.10, 1.3.6.1,1.3.6.2, 1.3.6.3, 1.3.6.4, 1.3.6.5, 1.3.6.6, 1.3.6.7, 1.3.6.8, 1.3.6.9,1.3.6.10, 1.3.7.1, 1.3.7.2, 1.3.7.3, 1.3.7.4, 1.3.7.5, 1.3.7.6, 1.3.7.7,1.3.7.8, 1.3.7.9, 1.3.7.10, 1.3.8.1, 1.3.8.2, 1.3.8.3, 1.3.8.4, 1.3.8.5,1.3.8.6, 1.3.8.7, 1.3.8.8, 1.3.8.9, 1.3.8.10, 1.3.9.1, 1.3.9.2, 1.3.9.3,1.3.9.4, 1.3.9.5, 1.3.9.6, 1.3.9.7, 1.3.9.8, 1.3.9.9, 1.3.9.10,1.3.10.1, 1.3.10.2, 1.3.10.3, 1.3.10.4, 1.3.10.5, 1.3.10.6, 1.3.10.7,1.3.10.8, 1.3.10.9, 1.3.10.10, 1.4.1.1, 1.4.1.2, 1.4.1.3, 1.4.1.4,1.4.1.5, 1.4.1.6, 1.4.1.7, 1.4.1.8, 1.4.1.9, 1.4.1.10, 1.4.2.1, 1.4.2.2,1.4.2.3, 1.4.2.4, 1.4.2.5, 1.4.2.6, 1.4.2.7, 1.4.2.8, 1.4.2.9, 1.4.2.10,1.4.3.1, 1.4.3.2, 1.4.3.3, 1.4.3.4, 1.4.3.5, 1.4.3.6, 1.4.3.7, 1.4.3.8,1.4.3.9, 1.4.3.10, 1.4.4.1, 1.4.4.2, 1.4.4.3, 1.4.4.4, 1.4.4.5, 1.4.4.6,1.4.4.7, 1.4.4.8, 1.4.4.9, 1.4.4.10, 1.4.5.1, 1.4.5.2, 1.4.5.3, 1.4.5.4,1.4.5.5, 1.4.5.6, 1.4.5.7, 1.4.5.8, 1.4.5.9, 1.4.5.10, 1.4.6.1, 1.4.6.2,1.4.6.3, 1.4.6.4, 1.4.6.5, 1.4.6.6, 1.4.6.7, 1.4.6.8, 1.4.6.9, 1.4.6.10,1.4.7.1, 1.4.7.2, 1.4.7.3, 1.4.7.4, 1.4.7.5, 1.4.7.6, 1.4.7.7, 1.4.7.8,1.4.7.9, 1.4.7.10, 1.4.8.1, 1.4.8.2, 1.4.8.3, 1.4.8.4, 1.4.8.5, 1.4.8.6,1.4.8.7, 1.4.8.8, 1.4.8.9, 1.4.8.10, 1.4.9.1, 1.4.9.2, 1.4.9.3, 1.4.9.4,1.4.9.5, 1.4.9.6, 1.4.9.7, 1.4.9.8, 1.4.9.9, 1.4.9.10, 1.4.10.1,1.4.10.2, 1.4.10.3, 1.4.10.4, 1.4.10.5, 1.4.10.6, 1.4.10.7, 1.4.10.8,1.4.10.9, 1.4.10.10, 1.5.1.1, 1.5.1.2, 1.5.1.3, 1.5.1.4, 1.5.1.5,1.5.1.6, 1.5.1.7, 1.5.1.8, 1.5.1.9, 1.5.1.10, 1.5.2.1, 1.5.2.2, 1.5.2.3,1.5.2.4, 1.5.2.5, 1.5.2.6, 1.5.2.7, 1.5.2.8, 1.5.2.9, 1.5.2.10, 1.5.3.1,1.5.3.2, 1.5.3.3, 1.5.3.4, 1.5.3.5, 1.5.3.6, 1.5.3.7, 1.5.3.8, 1.5.3.9,1.5.3.10, 1.5.4.1, 1.5.4.2, 1.5.4.3, 1.5.4.4, 1.5.4.5, 1.5.4.6, 1.5.4.7,1.5.4.8, 1.5.4.9, 1.5.4.10, 1.5.5.1, 1.5.5.2, 1.5.5.3, 1.5.5.4, 1.5.5.5,1.5.5.6, 1.5.5.7, 1.5.5.8, 1.5.5.9, 1.5.5.10, 1.5.6.1, 1.5.6.2, 1.5.6.3,1.5.6.4, 1.5.6.5, 1.5.6.6, 1.5.6.7, 1.5.6.8, 1.5.6.9, 1.5.6.10, 1.5.7.1,1.5.7.2, 1.5.7.3, 1.5.7.4, 1.5.7.5, 1.5.7.6, 1.5.7.7, 1.5.7.8, 1.5.7.9,1.5.7.10, 1.5.8.1, 1.5.8.2, 1.5.8.3, 1.5.8.4, 1.5.8.5, 1.5.8.6, 1.5.8.7,1.5.8.8, 1.5.8.9, 1.5.8.10, 1.5.9.1, 1.5.9.2, 1.5.9.3, 1.5.9.4, 1.5.9.5,1.5.9.6, 1.5.9.7, 1.5.9.8, 1.5.9.9, 1.5.9.10, 1.5.10.1, 1.5.10.2,1.5.10.3, 1.5.10.4, 1.5.10.5, 1.5.10.6, 1.5.10.7, 1.5.10.8, 1.5.10.9,1.5.10.10, 1.6.1.1, 1.6.1.2, 1.6.1.3, 1.6.1.4, 1.6.1.5, 1.6.1.6,1.6.1.7, 1.6.1.8, 1.6.1.9, 1.6.1.10, 1.6.2.1, 1.6.2.2, 1.6.2.3, 1.6.2.4,1.6.2.5, 1.6.2.6, 1.6.2.7, 1.6.2.8, 1.6.2.9, 1.6.2.10, 1.6.3.1, 1.6.3.2,1.6.3.3, 1.6.3.4, 1.6.3.5, 1.6.3.6, 1.6.3.7, 1.6.3.8, 1.6.3.9, 1.6.3.10,1.6.4.1, 1.6.4.2, 1.6.4.3, 1.6.4.4, 1.6.4.5, 1.6.4.6, 1.6.4.7, 1.6.4.8,1.6.4.9, 1.6.4.10, 1.6.5.1, 1.6.5.2, 1.6.5.3, 1.6.5.4, 1.6.5.5, 1.6.5.6,1.6.5.7, 1.6.5.8, 1.6.5.9, 1.6.5.10, 1.6.6.1, 1.6.6.2, 1.6.6.3, 1.6.6.4,1.6.6.5, 1.6.6.6, 1.6.6.7, 1.6.6.8, 1.6.6.9, 1.6.6.10, 1.6.7.1, 1.6.7.2,1.6.7.3, 1.6.7.4, 1.6.7.5, 1.6.7.6, 1.6.7.7, 1.6.7.8, 1.6.7.9, 1.6.7.10,1.6.8.1, 1.6.8.2, 1.6.8.3, 1.6.8.4, 1.6.8.5, 1.6.8.6, 1.6.8.7, 1.6.8.8,1.6.8.9, 1.6.8.10, 1.6.9.1, 1.6.9.2, 1.6.9.3, 1.6.9.4, 1.6.9.5, 1.6.9.6,1.6.9.7, 1.6.9.8, 1.6.9.9, 1.6.9.10, 1.6.10.1, 1.6.10.2, 1.6.10.3,1.6.10.4, 1.6.10.5, 1.6.10.6, 1.6.10.7, 1.6.10.8, 1.6.10.9, 1.6.10.10,1.7.1.1, 1.7.1.2, 1.7.1.3, 1.7.1.4, 1.7.1.5, 1.7.1.6, 1.7.1.7, 1.7.1.8,1.7.1.9, 1.7.1.10, 1.7.2.1, 1.7.2.2, 1.7.2.3, 1.7.2.4, 1.7.2.5, 1.7.2.6,1.7.2.7, 1.7.2.8, 1.7.2.9, 1.7.2.10, 1.7.3.1, 1.7.3.2, 1.7.3.3, 1.7.3.4,1.7.3.5, 1.7.3.6, 1.7.3.7, 1.7.3.8, 1.7.3.9, 1.7.3.10, 1.7.4.1, 1.7.4.2,1.7.4.3, 1.7.4.4, 1.7.4.5, 1.7.4.6, 1.7.4.7, 1.7.4.8, 1.7.4.9, 1.7.4.10,1.7.5.1, 1.7.5.2, 1.7.5.3, 1.7.5.4, 1.7.5.5, 1.7.5.6, 1.7.5.7, 1.7.5.8,1.7.5.9, 1.7.5.10, 1.7.6.1, 1.7.6.2, 1.7.6.3, 1.7.6.4, 1.7.6.5, 1.7.6.6,1.7.6.7, 1.7.6.8, 1.7.6.9, 1.7.6.10, 1.7.7.1, 1.7.7.2, 1.7.7.3, 1.7.7.4,1.7.7.5, 1.7.7.6, 1.7.7.7, 1.7.7.8, 1.7.7.9, 1.7.7.10, 1.7.8.1, 1.7.8.2,1.7.8.3, 1.7.8.4, 1.7.8.5, 1.7.8.6, 1.7.8.7, 1.7.8.8, 1.7.8.9, 1.7.8.10,1.7.9.1, 1.7.9.2, 1.7.9.3, 1.7.9.4, 1.7.9.5, 1.7.9.6, 1.7.9.7, 1.7.9.8,1.7.9.9, 1.7.9.10, 1.7.10.1, 1.7.10.2, 1.7.10.3, 1.7.10.4, 1.7.10.5,1.7.10.6, 1.7.10.7, 1.7.10.8, 1.7.10.9, 1.7.10.10, 1.8.1.1, 1.8.1.2,1.8.1.3, 1.8.1.4, 1.8.1.5, 1.8.1.6, 1.8.1.7, 1.8.1.8, 1.8.1.9, 1.8.1.10,1.8.2.1, 1.8.2.2, 1.8.2.3, 1.8.2.4, 1.8.2.5, 1.8.2.6, 1.8.2.7, 1.8.2.8,1.8.2.9, 1.8.2.10, 1.8.3.1, 1.8.3.2, 1.8.3.3, 1.8.3.4, 1.8.3.5, 1.8.3.6,1.8.3.7, 1.8.3.8, 1.8.3.9, 1.8.3.10, 1.8.4.1, 1.8.4.2, 1.8.4.3, 1.8.4.4,1.8.4.5, 1.8.4.6, 1.8.4.7, 1.8.4.8, 1.8.4.9, 1.8.4.10, 1.8.5.1, 1.8.5.2,1.8.5.3, 1.8.5.4, 1.8.5.5, 1.8.5.6, 1.8.5.7, 1.8.5.8, 1.8.5.9, 1.8.5.10,1.8.6.1, 1.8.6.2, 1.8.6.3, 1.8.6.4, 1.8.6.5, 1.8.6.6, 1.8.6.7, 1.8.6.8,1.8.6.9, 1.8.6.10, 1.8.7.1, 1.8.7.2, 1.8.7.3, 1.8.7.4, 1.8.7.5, 1.8.7.6,1.8.7.7, 1.8.7.8, 1.8.7.9, 1.8.7.10, 1.8.8.1, 1.8.8.2, 1.8.8.3, 1.8.8.4,1.8.8.5, 1.8.8.6, 1.8.8.7, 1.8.8.8, 1.8.8.9, 1.8.8.10, 1.8.9.1, 1.8.9.2,1.8.9.3, 1.8.9.4, 1.8.9.5, 1.8.9.6, 1.8.9.7, 1.8.9.8, 1.8.9.9, 1.8.9.10,1.8.10.1, 1.8.10.2, 1.8.10.3, 1.8.10.4, 1.8.10.5, 1.8.10.6, 1.8.10.7,1.8.10.8, 1.8.10.9, 1.8.10.10, 1.9.1.1, 1.9.1.2, 1.9.1.3, 1.9.1.4,1.9.1.5, 1.9.1.6, 1.9.1.7, 1.9.1.8, 1.9.1.9, 1.9.1.10, 1.9.2.1, 1.9.2.2,1.9.2.3, 1.9.2.4, 1.9.2.5, 1.9.2.6, 1.9.2.7, 1.9.2.8, 1.9.2.9, 1.9.2.10,1.9.3.1, 1.9.3.2, 1.9.3.3, 1.9.3.4, 1.9.3.5, 1.9.3.6, 1.9.3.7, 1.9.3.8,1.9.3.9, 1.9.3.10, 1.9.4.1, 1.9.4.2, 1.9.4.3, 1.9.4.4, 1.9.4.5, 1.9.4.6,1.9.4.7, 1.9.4.8, 1.9.4.9, 1.9.4.10, 1.9.5.1, 1.9.5.2, 1.9.5.3, 1.9.5.4,1.9.5.5, 1.9.5.6, 1.9.5.7, 1.9.5.8, 1.9.5.9, 1.9.5.10, 1.9.6.1, 1.9.6.2,1.9.6.3, 1.9.6.4, 1.9.6.5, 1.9.6.6, 1.9.6.7, 1.9.6.8, 1.9.6.9, 1.9.6.10,1.9.7.1, 1.9.7.2, 1.9.7.3, 1.9.7.4, 1.9.7.5, 1.9.7.6, 1.9.7.7, 1.9.7.8,1.9.7.9, 1.9.7.10, 1.9.8.1, 1.9.8.2, 1.9.8.3, 1.9.8.4, 1.9.8.5, 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10.1.1.9, 10.1.1.10, 10.1.2.1, 10.1.2.2, 10.1.2.3, 10.1.2.4,10.1.2.5, 10.1.2.6, 10.1.2.7, 10.1.2.8, 10.1.2.9, 10.1.2.10, 10.1.3.1,10.1.3.2, 10.1.3.3, 10.1.3.4, 10.1.3.5, 10.1.3.6, 10.1.3.7, 10.1.3.8,10.1.3.9, 10.1.3.10, 10.1.4.1, 10.1.4.2, 10.1.4.3, 10.1.4.4, 10.1.4.5,10.1.4.6, 10.1.4.7, 10.1.4.8, 10.1.4.9, 10.1.4.10, 10.1.5.1, 10.1.5.2,10.1.5.3, 10.1.5.4, 10.1.5.5, 10.1.5.6, 10.1.5.7, 10.1.5.8, 10.1.5.9,10.1.5.10, 10.1.6.1, 10.1.6.2, 10.1.6.3, 10.1.6.4, 10.1.6.5, 10.1.6.6,10.1.6.7, 10.1.6.8, 10.1.6.9, 10.1.6.10, 10.1.7.1, 10.1.7.2, 10.1.7.3,10.1.7.4, 10.1.7.5, 10.1.7.6, 10.1.7.7, 10.1.7.8, 10.1.7.9, 10.1.7.10,10.1.8.1, 10.1.8.2, 10.1.8.3, 10.1.8.4, 10.1.8.5, 10.1.8.6, 10.1.8.7,10.1.8.8, 10.1.8.9, 10.1.8.10, 10.1.9.1, 10.1.9.2, 10.1.9.3, 10.1.9.4,10.1.9.5, 10.1.9.6, 10.1.9.7, 10.1.9.8, 10.1.9.9, 10.1.9.10, 10.1.10.1,10.1.10.2, 10.1.10.3, 10.1.10.4, 10.1.10.5, 10.1.10.6, 10.1.10.7,10.1.10.8, 10.1.10.9, 10.1.10.10, 10.2.1.1, 10.2.1.2, 10.2.1.3,10.2.1.4, 10.2.1.5, 10.2.1.6, 10.2.1.7, 10.2.1.8, 10.2.1.9, 10.2.1.10,10.2.2.1, 10.2.2.2, 10.2.2.3, 10.2.2.4, 10.2.2.5, 10.2.2.6, 10.2.2.7,10.2.2.8, 10.2.2.9, 10.2.2.10, 10.2.3.1, 10.2.3.2, 10.2.3.3, 10.2.3.4,10.2.3.5, 10.2.3.6, 10.2.3.7, 10.2.3.8, 10.2.3.9, 10.2.3.10, 10.2.4.1,10.2.4.2, 10.2.4.3, 10.2.4.4, 10.2.4.5, 10.2.4.6, 10.2.4.7, 10.2.4.8,10.2.4.9, 10.2.4.10, 10.2.5.1, 10.2.5.2, 10.2.5.3, 10.2.5.4, 10.2.5.5,10.2.5.6, 10.2.5.7, 10.2.5.8, 10.2.5.9, 10.2.5.10, 10.2.6.1, 10.2.6.2,10.2.6.3, 10.2.6.4, 10.2.6.5, 10.2.6.6, 10.2.6.7, 10.2.6.8, 10.2.6.9,10.2.6.10, 10.2.7.1, 10.2.7.2, 10.2.7.3, 10.2.7.4, 10.2.7.5, 10.2.7.6,10.2.7.7, 10.2.7.8, 10.2.7.9, 10.2.7.10, 10.2.8.1, 10.2.8.2, 10.2.8.3,10.2.8.4, 10.2.8.5, 10.2.8.6, 10.2.8.7, 10.2.8.8, 10.2.8.9, 10.2.8.10,10.2.9.1, 10.2.9.2, 10.2.9.3, 10.2.9.4, 10.2.9.5, 10.2.9.6, 10.2.9.7,10.2.9.8, 10.2.9.9, 10.2.9.10, 10.2.10.1, 10.2.10.2, 10.2.10.3,10.2.10.4, 10.2.10.5, 10.2.10.6, 10.2.10.7, 10.2.10.8, 10.2.10.9,10.2.10.10, 10.3.1.1, 10.3.1.2, 10.3.1.3, 10.3.1.4, 10.3.1.5, 10.3.1.6,10.3.1.7, 10.3.1.8, 10.3.1.9, 10.3.1.10, 10.3.2.1, 10.3.2.2, 10.3.2.3,10.3.2.4, 10.3.2.5, 10.3.2.6, 10.3.2.7, 10.3.2.8, 10.3.2.9, 10.3.2.10,10.3.3.1, 10.3.3.2, 10.3.3.3, 10.3.3.4, 10.3.3.5, 10.3.3.6, 10.3.3.7,10.3.3.8, 10.3.3.9, 10.3.3.10, 10.3.4.1, 10.3.4.2, 10.3.4.3, 10.3.4.4,10.3.4.5, 10.3.4.6, 10.3.4.7, 10.3.4.8, 10.3.4.9, 10.3.4.10, 10.3.5.1,10.3.5.2, 10.3.5.3, 10.3.5.4, 10.3.5.5, 10.3.5.6, 10.3.5.7, 10.3.5.8,10.3.5.9, 10.3.5.10, 10.3.6.1, 10.3.6.2, 10.3.6.3, 10.3.6.4, 10.3.6.5,10.3.6.6, 10.3.6.7, 10.3.6.8, 10.3.6.9, 10.3.6.10, 10.3.7.1, 10.3.7.2,10.3.7.3, 10.3.7.4, 10.3.7.5, 10.3.7.6, 10.3.7.7, 10.3.7.8, 10.3.7.9,10.3.7.10, 10.3.8.1, 10.3.8.2, 10.3.8.3, 10.3.8.4, 10.3.8.5, 10.3.8.6,10.3.8.7, 10.3.8.8, 10.3.8.9, 10.3.8.10, 10.3.9.1, 10.3.9.2, 10.3.9.3,10.3.9.4, 10.3.9.5, 10.3.9.6, 10.3.9.7, 10.3.9.8, 10.3.9.9, 10.3.9.10,10.3.10.1, 10.3.10.2, 10.3.10.3, 10.3.10.4, 10.3.10.5, 10.3.10.6,10.3.10.7, 10.3.10.8, 10.3.10.9, 10.3.10.10, 10.4.1.1, 10.4.1.2,10.4.1.3, 10.4.1.4, 10.4.1.5, 10.4.1.6, 10.4.1.7, 10.4.1.8, 10.4.1.9,10.4.1.10, 10.4.2.1, 10.4.2.2, 10.4.2.3, 10.4.2.4, 10.4.2.5, 10.4.2.6,10.4.2.7, 10.4.2.8, 10.4.2.9, 10.4.2.10, 10.4.3.1, 10.4.3.2, 10.4.3.3,10.4.3.4, 10.4.3.5, 10.4.3.6, 10.4.3.7, 10.4.3.8, 10.4.3.9, 10.4.3.10,10.4.4.1, 10.4.4.2, 10.4.4.3, 10.4.4.4, 10.4.4.5, 10.4.4.6, 10.4.4.7,10.4.4.8, 10.4.4.9, 10.4.4.10, 10.4.5.1, 10.4.5.2, 10.4.5.3, 10.4.5.4,10.4.5.5, 10.4.5.6, 10.4.5.7, 10.4.5.8, 10.4.5.9, 10.4.5.10, 10.4.6.1,10.4.6.2, 10.4.6.3, 10.4.6.4, 10.4.6.5, 10.4.6.6, 10.4.6.7, 10.4.6.8,10.4.6.9, 10.4.6.10, 10.4.7.1, 10.4.7.2, 10.4.7.3, 10.4.7.4, 10.4.7.5,10.4.7.6, 10.4.7.7, 10.4.7.8, 10.4.7.9, 10.4.7.10, 10.4.8.1, 10.4.8.2,10.4.8.3, 10.4.8.4, 10.4.8.5, 10.4.8.6, 10.4.8.7, 10.4.8.8, 10.4.8.9,10.4.8.10, 10.4.9.1, 10.4.9.2, 10.4.9.3, 10.4.9.4, 10.4.9.5, 10.4.9.6,10.4.9.7, 10.4.9.8, 10.4.9.9, 10.4.9.10, 10.4.10.1, 10.4.10.2,10.4.10.3, 10.4.10.4, 10.4.10.5, 10.4.10.6, 10.4.10.7, 10.4.10.8,10.4.10.9, 10.4.10.10, 10.5.1.1, 10.5.1.2, 10.5.1.3, 10.5.1.4, 10.5.1.5,10.5.1.6, 10.5.1.7, 10.5.1.8, 10.5.1.9, 10.5.1.10, 10.5.2.1, 10.5.2.2,10.5.2.3, 10.5.2.4, 10.5.2.5, 10.5.2.6, 10.5.2.7, 10.5.2.8, 10.5.2.9,10.5.2.10, 10.5.3.1, 10.5.3.2, 10.5.3.3, 10.5.3.4, 10.5.3.5, 10.5.3.6,10.5.3.7, 10.5.3.8, 10.5.3.9, 10.5.3.10, 10.5.4.1, 10.5.4.2, 10.5.4.3,10.5.4.4, 10.5.4.5, 10.5.4.6, 10.5.4.7, 10.5.4.8, 10.5.4.9, 10.5.4.10,10.5.5.1, 10.5.5.2, 10.5.5.3, 10.5.5.4, 10.5.5.5, 10.5.5.6, 10.5.5.7,10.5.5.8, 10.5.5.9, 10.5.5.10, 10.5.6.1, 10.5.6.2, 10.5.6.3, 10.5.6.4,10.5.6.5, 10.5.6.6, 10.5.6.7, 10.5.6.8, 10.5.6.9, 10.5.6.10, 10.5.7.1,10.5.7.2, 10.5.7.3, 10.5.7.4, 10.5.7.5, 10.5.7.6, 10.5.7.7, 10.5.7.8,10.5.7.9, 10.5.7.10, 10.5.8.1, 10.5.8.2, 10.5.8.3, 10.5.8.4, 10.5.8.5,10.5.8.6, 10.5.8.7, 10.5.8.8, 10.5.8.9, 10.5.8.10, 10.5.9.1, 10.5.9.2,10.5.9.3, 10.5.9.4, 10.5.9.5, 10.5.9.6, 10.5.9.7, 10.5.9.8, 10.5.9.9,10.5.9.10, 10.5.10.1, 10.5.10.2, 10.5.10.3, 10.5.10.4, 10.5.10.5,10.5.10.6, 10.5.10.7, 10.5.10.8, 10.5.10.9, 10.5.10.10, 10.6.1.1,10.6.1.2, 10.6.1.3, 10.6.1.4, 10.6.1.5, 10.6.1.6, 10.6.1.7, 10.6.1.8,10.6.1.9, 10.6.1.10, 10.6.2.1, 10.6.2.2, 10.6.2.3, 10.6.2.4, 10.6.2.5,10.6.2.6, 10.6.2.7, 10.6.2.8, 10.6.2.9, 10.6.2.10, 10.6.3.1, 10.6.3.2,10.6.3.3, 10.6.3.4, 10.6.3.5, 10.6.3.6, 10.6.3.7, 10.6.3.8, 10.6.3.9,10.6.3.10, 10.6.4.1, 10.6.4.2, 10.6.4.3, 10.6.4.4, 10.6.4.5, 10.6.4.6,10.6.4.7, 10.6.4.8, 10.6.4.9, 10.6.4.10, 10.6.5.1, 10.6.5.2, 10.6.5.3,10.6.5.4, 10.6.5.5, 10.6.5.6, 10.6.5.7, 10.6.5.8, 10.6.5.9, 10.6.5.10,10.6.6.1, 10.6.6.2, 10.6.6.3, 10.6.6.4, 10.6.6.5, 10.6.6.6, 10.6.6.7,10.6.6.8, 10.6.6.9, 10.6.6.10, 10.6.7.1, 10.6.7.2, 10.6.7.3, 10.6.7.4,10.6.7.5, 10.6.7.6, 10.6.7.7, 10.6.7.8, 10.6.7.9, 10.6.7.10, 10.6.8.1,10.6.8.2, 10.6.8.3, 10.6.8.4, 10.6.8.5, 10.6.8.6, 10.6.8.7, 10.6.8.8,10.6.8.9, 10.6.8.10, 10.6.9.1, 10.6.9.2, 10.6.9.3, 10.6.9.4, 10.6.9.5,10.6.9.6, 10.6.9.7, 10.6.9.8, 10.6.9.9, 10.6.9.10, 10.6.10.1, 10.6.10.2,10.6.10.3, 10.6.10.4, 10.6.10.5, 10.6.10.6, 10.6.10.7, 10.6.10.8,10.6.10.9, 10.6.10.10, 10.7.1.1, 10.7.1.2, 10.7.1.3, 10.7.1.4, 10.7.1.5,10.7.1.6, 10.7.1.7, 10.7.1.8, 10.7.1.9, 10.7.1.10, 10.7.2.1, 10.7.2.2,10.7.2.3, 10.7.2.4, 10.7.2.5, 10.7.2.6, 10.7.2.7, 10.7.2.8, 10.7.2.9,10.7.2.10, 10.7.3.1, 10.7.3.2, 10.7.3.3, 10.7.3.4, 10.7.3.5, 10.7.3.6,10.7.3.7, 10.7.3.8, 10.7.3.9, 10.7.3.10, 10.7.4.1, 10.7.4.2, 10.7.4.3,10.7.4.4, 10.7.4.5, 10.7.4.6, 10.7.4.7, 10.7.4.8, 10.7.4.9, 10.7.4.10,10.7.5.1, 10.7.5.2, 10.7.5.3, 10.7.5.4, 10.7.5.5, 10.7.5.6, 10.7.5.7,10.7.5.8, 10.7.5.9, 10.7.5.10, 10.7.6.1, 10.7.6.2, 10.7.6.3, 10.7.6.4,10.7.6.5, 10.7.6.6, 10.7.6.7, 10.7.6.8, 10.7.6.9, 10.7.6.10, 10.7.7.1,10.7.7.2, 10.7.7.3, 10.7.7.4, 10.7.7.5, 10.7.7.6, 10.7.7.7, 10.7.7.8,10.7.7.9, 10.7.7.10, 10.7.8.1, 10.7.8.2, 10.7.8.3, 10.7.8.4, 10.7.8.5,10.7.8.6, 10.7.8.7, 10.7.8.8, 10.7.8.9, 10.7.8.10, 10.7.9.1, 10.7.9.2,10.7.9.3, 10.7.9.4, 10.7.9.5, 10.7.9.6, 10.7.9.7, 10.7.9.8, 10.7.9.9,10.7.9.10, 10.7.10.1, 10.7.10.2, 10.7.10.3, 10.7.10.4, 10.7.10.5,10.7.10.6, 10.7.10.7, 10.7.10.8, 10.7.10.9, 10.7.10.10, 10.8.1.1,10.8.1.2, 10.8.1.3, 10.8.1.4, 10.8.1.5, 10.8.1.6, 10.8.1.7, 10.8.1.8,10.8.1.9, 10.8.1.10, 10.8.2.1, 10.8.2.2, 10.8.2.3, 10.8.2.4, 10.8.2.5,10.8.2.6, 10.8.2.7, 10.8.2.8, 10.8.2.9, 10.8.2.10, 10.8.3.1, 10.8.3.2,10.8.3.3, 10.8.3.4, 10.8.3.5, 10.8.3.6, 10.8.3.7, 10.8.3.8, 10.8.3.9,10.8.3.10, 10.8.4.1, 10.8.4.2, 10.8.4.3, 10.8.4.4, 10.8.4.5, 10.8.4.6,10.8.4.7, 10.8.4.8, 10.8.4.9, 10.8.4.10, 10.8.5.1, 10.8.5.2, 10.8.5.3,10.8.5.4, 10.8.5.5, 10.8.5.6, 10.8.5.7, 10.8.5.8, 10.8.5.9, 10.8.5.10,10.8.6.1, 10.8.6.2, 10.8.6.3, 10.8.6.4, 10.8.6.5, 10.8.6.6, 10.8.6.7,10.8.6.8, 10.8.6.9, 10.8.6.10, 10.8.7.1, 10.8.7.2, 10.8.7.3, 10.8.7.4,10.8.7.5, 10.8.7.6, 10.8.7.7, 10.8.7.8, 10.8.7.9, 10.8.7.10, 10.8.8.1,10.8.8.2, 10.8.8.3, 10.8.8.4, 10.8.8.5, 10.8.8.6, 10.8.8.7, 10.8.8.8,10.8.8.9, 10.8.8.10, 10.8.9.1, 10.8.9.2, 10.8.9.3, 10.8.9.4, 10.8.9.5,10.8.9.6, 10.8.9.7, 10.8.9.8, 10.8.9.9, 10.8.9.10, 10.8.10.1, 10.8.10.2,10.8.10.3, 10.8.10.4, 10.8.10.5, 10.8.10.6, 10.8.10.7, 10.8.10.8,10.8.10.9, 10.8.10.10, 10.9.1.1, 10.9.1.2, 10.9.1.3, 10.9.1.4, 10.9.1.5,10.9.1.6, 10.9.1.7, 10.9.1.8, 10.9.1.9, 10.9.1.10, 10.9.2.1, 10.9.2.2,10.9.2.3, 10.9.2.4, 10.9.2.5, 10.9.2.6, 10.9.2.7, 10.9.2.8, 10.9.2.9,10.9.2.10, 10.9.3.1, 10.9.3.2, 10.9.3.3, 10.9.3.4, 10.9.3.5, 10.9.3.6,10.9.3.7, 10.9.3.8, 10.9.3.9, 10.9.3.10, 10.9.4.1, 10.9.4.2, 10.9.4.3,10.9.4.4, 10.9.4.5, 10.9.4.6, 10.9.4.7, 10.9.4.8, 10.9.4.9, 10.9.4.10,10.9.5.1, 10.9.5.2, 10.9.5.3, 10.9.5.4, 10.9.5.5, 10.9.5.6, 10.9.5.7,10.9.5.8, 10.9.5.9, 10.9.5.10, 10.9.6.1, 10.9.6.2, 10.9.6.3, 10.9.6.4,10.9.6.5, 10.9.6.6, 10.9.6.7, 10.9.6.8, 10.9.6.9, 10.9.6.10, 10.9.7.1,10.9.7.2, 10.9.7.3, 10.9.7.4, 10.9.7.5, 10.9.7.6, 10.9.7.7, 10.9.7.8,10.9.7.9, 10.9.7.10, 10.9.8.1, 10.9.8.2, 10.9.8.3, 10.9.8.4, 10.9.8.5,10.9.8.6, 10.9.8.7, 10.9.8.8, 10.9.8.9, 10.9.8.10, 10.9.9.1, 10.9.9.2,10.9.9.3, 10.9.9.4, 10.9.9.5, 10.9.9.6, 10.9.9.7, 10.9.9.8, 10.9.9.9,10.9.9.10, 10.9.10.1, 10.9.10.2, 10.9.10.3, 10.9.10.4, 10.9.10.5,10.9.10.6, 10.9.10.7, 10.9.10.8, 10.9.10.9, 10.9.10.10, 10.10.1.1,10.10.1.2, 10.10.1.3, 10.10.1.4, 10.10.1.5, 10.10.1.6, 10.10.1.7,10.10.1.8, 10.10.1.9, 10.10.1.10, 10.10.2.1, 10.10.2.2, 10.10.2.3,10.10.2.4, 10.10.2.5, 10.10.2.6, 10.10.2.7, 10.10.2.8, 10.10.2.9,10.10.2.10, 10.10.3.1, 10.10.3.2, 10.10.3.3, 10.10.3.4, 10.10.3.5,10.10.3.6, 10.10.3.7, 10.10.3.8, 10.10.3.9, 10.10.3.10, 10.10.4.1,10.10.4.2, 10.10.4.3, 10.10.4.4, 10.10.4.5, 10.10.4.6, 10.10.4.7,10.10.4.8, 10.10.4.9, 10.10.4.10, 10.10.5.1, 10.10.5.2, 10.10.5.3,10.10.5.4, 10.10.5.5, 10.10.5.6, 10.10.5.7, 10.10.5.8, 10.10.5.9,10.10.5.10, 10.10.6.1, 10.10.6.2, 10.10.6.3, 10.10.6.4, 10.10.6.5,10.10.6.6, 10.10.6.7, 10.10.6.8, 10.10.6.9, 10.10.6.10, 10.10.7.1,10.10.7.2, 10.10.7.3, 10.10.7.4, 10.10.7.5, 10.10.7.6, 10.10.7.7,10.10.7.8, 10.10.7.9, 10.10.7.10, 10.10.8.1, 10.10.8.2, 10.10.8.3,10.10.8.4, 10.10.8.5, 10.10.8.6, 10.10.8.7, 10.10.8.8, 10.10.8.9,10.10.8.10, 10.10.9.1, 10.10.9.2, 10.10.9.3, 10.10.9.4, 10.10.9.5,10.10.9.6, 10.10.9.7, 10.10.9.8, 10.10.9.9, 10.10.9.10, 10.10.10.1,10.10.10.2, 10.10.10.3, 10.10.10.4, 10.10.10.5, 10.10.10.6, 10.10.10.7,10.10.10.8, 10.10.10.9, 10.10.10.10

Additional exemplary formula B compound groups include the followingcompound groups disclosed below. Unless otherwise specified, theconfigurations of all hydrogen atoms and R groups for the followingcompound groups are as defined for the group 1 compounds of formula Babove. As is apparent from the description, each of the compound groupsdisclose a significant number of unique compounds or generic structures.The compounds or generic structures specifically described in any of thecompound groups are thus exemplary only and the remaining compounds orstructures in each group are described by Tables A and B as noted ineach group.

As used in the description of compounds in the compound groups, thedefinitive structure of compounds in the various compound groups isspecified only by the structure defining portion of the compound groupand in Tables A and B, which together definitively name or specifiesindividual compound or genus structures. The structure defining portionof the compound groups is generally contained in the first sentence thecompound groups below. This applies regardless of any name or structure,including chemical names in the exemplary compounds that are named insome of the compound groups. Thus, any name or structure for anycompound or compound genus that refers to a compound or genus in acompound group and is given anywhere in the disclosure is intended onlyto refer to the compound or genus that is definitively specified by thecompound groups together with Tables A and B.

Group 2. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that R^(10E) is hydrogen in the β-configuration.Exemplary compounds include 3β, 17β-dihydroxy-5β-androstane, 3β,17β-dihydroxy-7β-methyl-5β-androstane, 3β,17β-dihydroxy-7β-methoxy-5β-androstane, 3β,7β,17β-trihydroxy-5β-androstane, 3β-amino-17β-hydroxy-5β-androstane3β-amino-7β, 17β-dihydroxy-5β-androstane,3β-hydroxy-17β-amino-5β-androstane,3β,7β-dihydroxy-17β-amino-5β-androstane and 16α-hydroxy, 16-methylene(═CH₂), 16-oxo and 16α-halo analogs of any of these compounds.

Group 3. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that a double bond at the 5-6 position is present.Exemplary compounds include 3β, 17β-dihydroxyandrost-5-ene (compound1.1.5.9), 3β, 17β-dihydroxy-7β-methylandrost-5-ene, 3β,17β-dihydroxy-7β-methoxyandrost-5-ene, 3β,7β,17β-trihydroxyandrost-5-ene, 3β-amino-17β-hydroxyandrost-5-ene3β-amino-7β, 17β-dihydroxyandrost-5-ene,3β-hydroxy-17β-aminoandrost-5-ene (compound 1.1.5.1),3β,7β-dihydroxy-17β-aminoandrost-5-ene and 16α-hydroxy, 16-methylene,16-oxo and 16α-halo analogs of any of these compounds.

Group 4. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus as described for group 1compounds, except that double bonds at the 1-2- and 5-6 positions arepresent. Exemplary compounds include 3β, 17β-dihydroxyandrost-1,5-diene,3β, 17β-dihydroxy-7β-methylandrost-1,5-diene, 3β,17β-dihydroxy-7β-methoxyandrost-1,5-diene, 3β,7β,17β-trihydroxyandrost-1,5-diene, 3β-amino-17β-hydroxyandrost-1,5-diene3β-amino-7β, 17β-dihydroxyandrost-1,5-diene,3β-hydroxy-17β-aminoandrost-1,5-diene,3β,7β-dihydroxy-17β-aminoandrost-1,5-diene and 16α-hydroxy,16-methylene, 16-oxo and 16α-halo analogs of any of these compounds.

Group 5. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that a double bond at the 1-2 position is present.Exemplary compounds include 3β, 17β-dihydroxyandrost-1-ene, 3β,17β-dihydroxy-7β-methylandrost-1-ene, 3β,17β-dihydroxy-7β-methoxyandrost-1-ene, 3β,7β,17β-trihydroxyandrost-1-ene, 3β-amino-17β-hydroxyandrost-1-ene3β-amino-7β, 17β-dihydroxyandrost-1-ene,3β-hydroxy-17β-aminoandrost-1-ene,3β,7β-dihydroxy-17β-aminoandrost-1-ene and 16α-hydroxy, 16-methylene,16-oxo and 16α-halo analogs of any of these compounds.

Group 5A. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that a double bond at the 1-2 position is present andhydrogen at the 5-position is in the β-configuration.

Exemplary compounds include 3β, 17β-dihydroxy-5β-androst-1-ene, 3β,17β-dihydroxy-7β-methyl-5β-androst-1-ene, 3β,17β-dihydroxy-7β-methoxy-5β-androst-1-ene, 3β,7β,17β-trihydroxy-5β-androst-1-ene, 3β-amino-17β-hydroxy-5β-androst-1-ene3β-amino-7β, 17β-dihydroxy-5β-androst-1-ene,3β-hydroxy-17β-amino-5β-androst-1-ene,3β,7β-dihydroxy-17β-amino-5β-androst-1-ene and 16α-hydroxy,16-methylene, 16-oxo and 16α-halo analogs of any of these compounds.

Group 6. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that a double bond at the 4-5 position is present.Exemplary compounds include 3β, 17β-dihydroxyandrost-4-ene, 3β,17β-dihydroxy-7β-methylandrost-4-ene, 3β,17β-dihydroxy-7β-methoxyandrost-4-ene, 3β,7β,17β-trihydroxyandrost-4-ene, 3β-amino-17β-hydroxyandrost-4-ene3β-amino-7β, 17β-dihydroxyandrost-4-ene,3β-hydroxy-17β-aminoandrost-4-ene,3β,7β-dihydroxy-17β-aminoandrost-4-ene and 16α-hydroxy, 16-methylene,16-oxo and 16α-halo analogs of any of these compounds.

Group 7. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that double bonds at both the 1-2 and 4-5 positionsare present. Exemplary compounds include 3β,17β-dihydroxyandrost-1,4-diene, 3β,17β-dihydroxy-7β-methylandrost-1,4-diene, 3β,17β-dihydroxy-7β-methoxyandrost-1,4-diene, 3β,7β,17β-trihydroxyandrost-1,4-diene, 3β-amino-17β-hydroxyandrost-1,4-diene3β-amino-7β, 17β-dihydroxyandrost-1,4-diene,3β-hydroxy-17β-aminoandrost-1,4-diene,3β,7β-dihydroxy-17β-aminoandrost-1,4-diene and 16α-hydroxy,16-methylene, 16-oxo and 16α-halo analogs of any of these compounds.

Group 8. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that a double bond at the 16-17 position is present.For this group and other compound groups that contain a 16-17 doublebond, the R³ and R⁴ moieties will only be single bonded. Moieties suchas ═O are thus not included as R³ or R⁴ substituents in the compoundgroup, since this would give rise to a pentavalent carbon at the 16- or17-position. Group 8 compound 1.2.7.1 does not represent any compoundsince a 16-17 double bond and an ═O at 16 can not both be present at thesame time. Exemplary compounds include 3β,17-dihydroxy-5α-androst-16-ene, 3β,17-dihydroxy-7β-methyl-5α-androst-16-ene, 3β,17-dihydroxy-7β-methoxy-5α-androst-16-ene, 3β,7β,17-trihydroxy-5α-androst-16-ene, 3β-amino-17-hydroxy-5α-androst-16-ene3β-amino-7β, 17-dihydroxy-5α-androst-16-ene,3β-hydroxy-17-amino-5α-androst-16-ene,3β,7β-dihydroxy-17-amino-5α-androst-16-ene and 16-hydroxy, and 16-haloanalogs of any of these compounds. Since a double bond is present at the16-17 position, there are no 16-oxo or 16-methylene compounds in thisgroup, or in other groups, e.g., groups 8A, 9 or 10 below, where adouble bond is present at the 16-17 position. Thus, group 8 compound1.1.7.1 and 1.1.10.1 are not included in group 8.

Group 8A. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that a double bond at the 16-17 position is presentand hydrogen at the 5-position is in the β-configuration. Exemplarycompounds include 3β, 17-dihydroxy-5β-androst-16-ene, 3β,17-dihydroxy-7β-methyl-5β-androst-16-ene, 3β,17-dihydroxy-7β-methoxy-5β-androst-16-ene, 3β,7β,17-trihydroxy-5β-androst-16-ene, 3β-amino-17-hydroxy-5β-androst-16-ene3β-amino-7β, 17-dihydroxy-5β-androst-16-ene,3β-hydroxy-17-amino-5β-androst-16-ene,3β,7β-dihydroxy-17-amino-5β-androst-16-ene and 16-hydroxy and 16-haloanalogs of any of these compounds.

Group 9. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that double bonds at the 16-17 and 5-6 positions arepresent. Exemplary compounds include 3β, 17-dihydroxyandrost-5,16-diene,3β, 17-dihydroxy-7β-methylandrost-5,16-diene, 3β,17-dihydroxy-7β-methoxyandrost-5,16-diene, 3β,7β,17-trihydroxyandrost-5,16-diene, 3β-amino-17-hydroxyandrost-5,16-diene3β-amino-7β, 17-dihydroxyandrost-5,16-diene,3β-hydroxy-17-aminoandrost-5,16-diene,3β,7β-dihydroxy-17-aminoandrost-5,16-diene and 16-hydroxy and 16-haloanalogs of any of these compounds.

Group 10. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that double bonds at the 16-17 and 1-2 positions arepresent. Exemplary compounds include 3β,17-dihydroxy-5α-androst-1,16-ene, 3β,17-dihydroxy-7β-methyl-5α-androst-1,16-ene, 3β,17-dihydroxy-7β-methoxy-5α-androst-1,16-ene, 3β,7β,17-trihydroxy-5α-androst-1,16-ene,3β-amino-17-hydroxy-5α-androst-1,16-ene 3β-amino-7β,17-dihydroxy-5α-androst-1,16-ene,3β-hydroxy-17-amino-5α-androst-1,16-ene,3β,7β-dihydroxy-17-amino-5α-androst-1,16-ene and 16-hydroxy and 16-haloanalogs of any of these compounds.

Group 10A. This group comprises compounds named in Table B having R¹,R², R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ andR⁴ substituents are bonded to the steroid nucleus described for group 1compounds, except that a double bond at the 16-17 and 1-2 positions arepresent and hydrogen at the 5-position is in the β-configuration.Exemplary compounds include 3β, 17-dihydroxy-5β-androst-1,16-ene, 3β,17-dihydroxy-7β-methyl-5β-androst-1,16-ene, 3β,17-dihydroxy-7β-methoxy-5β-androst-1,16-ene, 3β,7β,17-trihydroxy-5β-androst-1,16-ene,3β-amino-17-hydroxy-5β-androst-1,16-ene 3β-amino-7β,17-dihydroxy-5β-androst-1,16-ene,3β-hydroxy-17-amino-5β-androst-1,16-ene,3β,7β-dihydroxy-17-amino-5β-androst-1,16-ene and 16-hydroxy and 16-haloanalogs of any of these compounds.

Group 11. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that double bonds at the 16-17 and 4-5 positions arepresent. Exemplary compounds include 3β, 17-dihydroxyandrost-4,16-diene,3β, 17-dihydroxy-7β-methylandrost-4,16-diene, 3β,17-dihydroxy-7β-methoxyandrost-4,16-diene, 3β,7β,17-trihydroxyandrost-4,16-diene, 3β-amino-17-hydroxyandrost-4,16-diene3β-amino-7β, 17-dihydroxyandrost-4,16-diene,3β-hydroxy-17-aminoandrost-4,16-diene,3β,7β-dihydroxy-17-aminoandrost-4,16-diene and 16-hydroxy and 16-haloanalogs of any of these compounds.

Group 12. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that double bonds at the 1-2, 16-17 and 4-5 positionsare present. Exemplary compounds include 3β,17-dihydroxyandrost-1,4,16-triene, 3β,17-dihydroxy-7β-methylandrost-1,4,16-triene, 3β,17-dihydroxy-7β-methoxyandrost-1,4,16-triene, 3β,7β,17-trihydroxyandrost-1,4,16-triene,3β-amino-17-hydroxyandrost-1,4,16-triene 3β-amino-7β,17-dihydroxyandrost-1,4,16-triene,3β-hydroxy-17-aminoandrost-1,4,16-triene,3β,7β-dihydroxy-17-aminoandrost-1,4,16-triene and 16-hydroxy, and16-halo analogs of any of these compounds.

Group 13. This group comprises compounds named in Table B having R¹, R²,R³ and R⁴ substituents defined in Table A wherein the R¹, R², R³ and R⁴substituents are bonded to the steroid nucleus described for group 1compounds, except that double bonds at the 1-2, 16-17 and 5-6 positionsare present. Exemplary compounds include 3β,17-dihydroxyandrost-1,5,16-triene, 3β,17-dihydroxy-7β-methylandrost-1,5,16-triene, 3β,17-dihydroxy-7β-methoxyandrost-1,5,16-triene, 3β,7β,17-trihydroxyandrost-1,5,16-triene,3β-amino-17-hydroxyandrost-1,5,16-triene 3β-amino-7β,17-dihydroxyandrost-1,5,16-triene,3β-hydroxy-17-aminoandrost-1,5,16-triene,3β,7β-dihydroxy-17-aminoandrost-1,5,16-triene and 16-hydroxy, and16-halo analogs of any of these compounds.

Group 14. This group contains compounds from groups 1-13 above wherein,for single bonded R¹, R², R³ and R⁴ moieties, R¹, R², R³ and R⁴respectively are in the α,β,α,β, β,β,α,α, β,α,α,β, α,α,α,β, β,β,β,β,β,β,β,α, α,β,β,β, β,α,α,α, β,α,β,β, α,α,α,α, β,α,β,α, α,β,β,α, α,α,β,α,α,β,α,α or α,α,β,β configurations. Thus, R¹, R², R³ and R⁴ respectivelymay be, for example, in the α,β,α,β configurations or in the β,β,α,αconfigurations or in the β,β,β,β configurations respectively or in theα,β,β,β configurations respectively or in the α,β,β,α configurationsrespectively.

Thus, when R¹, R², R³ and R⁴ respectively are in the α,β,α,βconfigurations, group 14 compound 1.2.7.1 from group 3 (also referred toas group 14-3 compound 1.2.7.1) is3α,7β-dihydroxy-16-oxo-17β-aminoandrost-5-ene and compound 1.1.4.1 fromgroup 3 (also referred to as group 14-3 compound 1.1.4.1) is3α-hydroxy-16α-fluoro-17β-aminoandrost-5-ene. When R¹, R², R³ and R⁴respectively are in the α,β,α,β configurations, group 14 compound1.2.7.1 from group 1 (also referred to as group 14-1 compound 1.2.7.1)is 3α,7β-dihydroxy-16-oxo-17β-aminoandrostane and group 14-1 compound1.1.4.1 is 3α-hydroxy-16α-fluoro-17β-aminoandrostane. Similarly, whenR¹, R², R³ and R⁴ respectively are in the α,β,α,β configurations, group14-6 compound 1.2.7.1 is 3α,7β-dihydroxy-16-oxo-17β-aminoandrost-4-eneand group 14-6 compound 1.1.4.1 is3α-hydroxy-16α-fluoro-17β-aminoandrost-4-ene.

Similarly, when R¹, R², R³ and R⁴ respectively are in the α,β,β,αconfigurations, group 14-3 compound 1.2.6.1 is3α,7β,16β-trihydroxy-17α-aminoandrost-5-ene and group 14-3 compound1.1.4.1 is 3α-hydroxy-16β-fluoro-17β-aminoandrost-5-ene. When R¹, R², R³and R⁴ respectively are in the β,β,α,α configurations, group 14-3compound 1.2.6.1 is 3β,7β,16α-trihydroxy-17α-aminoandrost-5-ene andgroup 14-3 compound 1.1.4.1 is3β-hydroxy-16α-fluoro-17α-aminoandrost-5-ene. When R¹, R², R³ and R⁴respectively are in the α,β,β,α configurations, group 14-4 compound1.2.6.1 is 3α,7β,16β-trihydroxy-17α-aminoandrost-1,5-diene and group14-4 compound 1.1.4.1 is3α-hydroxy-16β-fluoro-17β-aminoandrost-1,5-diene. When R¹, R², R³ and R⁴respectively are in the β,β,α,α configurations, group 14-4 compound1.2.6.1 is 3β,7β,16α-trihydroxy-17α-aminoandrost-1,5-diene and group14-4 compound 1.1.4.1 is3β-hydroxy-16α-fluoro-17α-aminoandrost-1,5-diene. When R¹, R², R³ and R⁴respectively are in the α,β,β,α configurations, group 14-2 compound1.2.6.1 is 3α,7β,16β-trihydroxy-17α-amino-5β-androstane and group 14-2compound 1.1.4.1 is 3α-hydroxy-16β-fluoro-17α-amino-5β-androstane. WhenR¹, R², R³ and R⁴ respectively are in the β,β,α,α configurations, group14-2 compound 1.2.6.1 is 3β,7β,16α-trihydroxy-17α-amino-5β-androstaneand group 14-2 compound 1.1.4.1 is3β-hydroxy-16α-fluoro-17α-amino-5β-androstane. When R¹, R², R³ and R⁴respectively are in the α,β,α,β configurations, group 14-2 compound1.2.6.1 is 3α,7β,16α-trihydroxy-17β-amino-5β-androstane and group 14-2compound 1.1.4.1 is 3α-hydroxy-16β-fluoro-17β-amino-5β-androstane. WhenR¹, R², R³ and R⁴ respectively are in the β,β,β,α configurations, group14-2 compound 1.2.6.1 is 3β,7β,16β-trihydroxy-17α-amino-5β-androstaneand group 14-2 compound 1.1.4.1 is3β-hydroxy-16β-fluoro-17α-amino-5β-androstane. Compounds in othergroups, e.g., groups 14-5, 14-5A, 14-6, 14-7, 14-8, 14-8A, 14-9, 14-10,14-10A, 14-11, 14-12 or 14-13, where R¹, R², R³ and R⁴ respectively arein the listed configurations, e.g., α,β,α,β, β,β,β,α, β,β,α,α orβ,β,β,β, are named or described in the same manner.

Group 15. This group contains compounds in groups 1-14 above whereinR^(10F), R^(10G) and R^(10H) respectively are in the β,α,β, β,β,α,α,β,β, β,β,β, α,α,α, α,β,α or α,α,β configurations. Thus, when R^(10F),R^(10G) and R^(10H) respectively can be in the β,α,β configurations.Group 15 compounds include groups 15-1 through 15-14-13. Groups 15-1,15-2, 15-3, 15-4, 15-5, 15-5A, 15-6, 15-7, 15-8, 15-8A, 15-9, 15-10,15-10A, 15-11, 15-12 and 15-13 are compounds as described in groups 1through 13 respectively, but where R^(10F), R^(10G) and R^(10H)respectively are in the listed configurations respectively, e.g., theβ,α,β or β,β,α configurations, instead of being in the β,α,αconfigurations shown in groups 1 through 13. Similarly, compound groups15-14-1, 15-14-2, 15-14-3, 15-14-4, 15-14-5, 15-14-5A, 15-14-6, 15-14-7,15-14-8, 15-14-8A, 15-14-9, 15-14-10, 15-14-10A, 15-14-11, 15-14-12 and15-14-11 are compounds as described in group 14 where (1) where R^(10F),R^(10G) and R^(10H) respectively are in the listed configurationsrespectively, e.g., the β,α,β or β,β,α configurations, and (2) R¹, R²,R³ and R⁴ respectively are in the listed configurations, e.g., theα,β,α,β, β,α,α,β, β,β,β,α, β,β,α,α or β,β,β,β configurations, asdescribed in group 14.

Group 16. This group contains compounds in groups 1-15 above wherein 1,2, 3 or 4 of R^(10A), R^(10B), R^(10C) and R^(10D) are not —H and are anindependently chosen moiety as defined herein, e.g., optionallysubstituted alkyl such as methyl, ethyl, fluoromethyl or hydroxymethyl,—F, —Cl, —Br, —I, —SR^(PR), —OR^(PR), —N(R^(PR))₂, —OH, ═O, —SH, ═S,—NH₂, —NHCH₃, —N(CH₃)₂, ═NOH, ═NCH₃, ether, thioether, ester, carbamate,amide, optionally substituted heterocycle, optionally substitutedmonosaccharide or optionally substituted oligosaccharide, wherein eachR^(10A), R^(10B), R^(10C) and R^(10D) is independently in theα-configuration or the β-configuration and R^(PR) independently are —Hor a protecting group. Thus, when R^(10C) and R^(10D) are both not —H,they can be in the β,β, β,α, α,β or α,α configurations respectively,when they are linked by a single bond. Similarly, when R^(10B) andR^(10D) are both not —H, they can be in the β,β, β,α, α,β or α,αconfigurations respectively, or, when R^(10B) is not —H and R^(10A),R^(10C) and R^(10D) are all —H, R^(10B) can be in the α-configuration orthe β-configuration.

This group includes groups 16-1 through 16-15-14-13. These compoundgroups include (1) 16-1, 16-2, 16-3, 16-4, 16-5, 16-5A, 16-6, 16-7,16-8, 16-8A, 16-9, 16-10, 16-10A, 16-11, 16-12 and 16-13, which arecompounds in groups 1 through 13 where one or more of R^(10A), R^(10B),R^(10C) and R^(10D) are substituted, (2) 16-14-1, 16-14-2, 16-14-3,16-14-4, 16-14-5, 16-14-5A, 16-14-6, 16-14-7, 16-14-8, 16-14-8A,16-14-9, 16-14-10, 16-14-10A, 16-14-11, 16-14-12 and 16-14-13, which arethe group 14 compounds where one or more of R^(10A), R^(10B), R^(10C)and R^(10D) are substituted and where R¹, R², R³ and R⁴ are in theconfigurations specified in group 14, e.g., α,β,α,β, β,β,β,β, α,β,β,α orβ,β,α,α, (3) 16-15-1, 16-15-2, 16-15-3, 16-15-4, 16-15-5, 16-15-5A,16-15-6, 16-15-7, 16-15-8, 16-15-8A, 16-15-9, 16-15-10, 16-15-10A,16-15-11, 16-15-12 and 16-15-13, which are the group 16 compounds and(4) groups 16-15-14-1, 16-15-14-2, 16-15-14-3, 16-15-14-4, 16-15-14-5,16-15-14-5A, 16-15-14-6, 16-15-14-7, 16-15-14-8, 16-15-14-8A,16-15-14-9, 16-15-14-10, 16-15-14-10A, 16-15-14-11, 16-15-14-12 and16-15-14-13, which are group 14 compounds in group 15.

Group 17. This group contains compounds in groups 1-16 above wherein (1)one or both of R⁵ and R⁶ are not —CH₃ and they independently are amoiety as defined herein, and (2) R⁵ and R⁶ are in the β,β, β,α, α,β orα,α configurations respectively. Thus, R⁵ and R⁶ independently can be—H, —CH₃, —C₂H₅, —C₃H₇, optionally substituted alkyl, —OH, —F, —Cl, —Br,—I or another single bonded moiety as defined herein in the β,β, β,α,α,β or α,α configurations. Thus, for example, R⁵ can be —CH₃, —CH₂OH,—CHO or —C₂H₅ and R⁶ can be —H, where both are in the β-configuration orR⁵ can be optionally substituted alkyl and R⁶ can be —H, where both arein, e.g., the β,α or α,β configurations respectively instead of bothbeing in the β-configuration as in groups 1 through 16.

This group includes groups 17-1 through 17-16-15-14-13. These compoundgroups include (1) 17-1, 17-2, 17-3, 17-4, 17-5, 17-5A, 17-6, 17-7,17-8, 17-8A, 17-9, 17-10, 17-10A, 17-11, 17-12 and 17-13, which arecompounds in groups 1 through 13 where one or both of R⁵ and R⁶ are not—CH₃, e.g., R⁵ is —H, —C₂H₅, —CH₂OH and R⁶ is —H, —CH₃, —CH₂OH, —CH₂F or—C₂H₅, and they independently are a moiety as defined herein, and whereR⁵ and R⁶ are in the β,β, β,α, α,β or α,α configurations respectively,(2) 17-14-1, 17-14-2, 17-14-3, 17-14-4, 17-14-5, 17-14-5A, 17-14-6,17-14-7, 17-14-8, 17-14-8A, 17-14-9, 17-14-10, 17-14-10A, 17-14-11,17-14-12 and 17-14-13, which are compounds in group 14 where one or bothof R⁵ and R⁶ are not —CH₃ and are optionally in other configurationsthan is shown for group 1 and where R¹, R², R³ and R⁴ are in theconfigurations described in group 14, e.g., α,β,α,β, β,β,β,β, β,β,β,α orβ,β,α,α respectively, (3) 17-15-1, 17-15-2, 17-15-3, 17-15-4, 17-15-5,17-15-5A, 17-15-6, 17-15-7, 17-15-8, 17-15-8A, 17-15-9, 17-15-10,17-15-10A, 17-15-11, 17-15-12 and 17-15-13, which are compounds in group15 where one or both of R⁵ and R⁶ are not —CH₃ and are optionally inother configurations than is shown for group 1, (4) 17-16-1, 17-16-2,17-16-3, 17-16-4, 17-16-5, 17-16-5A, 17-16-6, 17-16-7, 17-16-8,17-16-8A, 17-16-9, 17-16-10, 17-16-10A, 17-16-11, 17-16-12 and 17-16-13,which are compounds in group 16 where one or both of R⁵ and R⁶ are not—CH₃ and are optionally in other configurations than is shown for group1, (5) 17-16-14-1, 17-16-14-2, 17-16-14-3, 17-16-14-4, 17-16-14-5,17-16-14-5A, 17-16-14-6, 17-16-14-7, 17-16-14-8, 17-16-14-8A,17-16-14-9, 17-16-14-10, 17-16-14-10A, 17-16-14-11, 17-16-14-12 and17-16-14-13, which are the group 14 compounds in group 16 where one ormore of R^(10A), R^(10B), R^(10C) and R^(10D) are substituted and whereR¹, R², R³ and R⁴ are in the configurations specified in group 14, e.g.,α,β,α,β, β,β,β,β, α,β,β,α or β,β,α,α respectively, (6) 17-15-14-1,17-15-14-2, 17-15-14-3, 17-15-14-4, 17-15-14-5, 17-15-14-5A, 17-15-14-6,17-15-14-7, 17-15-14-8, 17-15-14-8A, 17-15-14-9, 17-15-14-10,17-15-14-10A, 17-15-14-11, 17-15-14-12 and 17-15-14-13, which are thegroup 14 compounds in group 15 where one or more of R^(10A), R^(10B),R^(10C) and R^(10D) are substituted and where R¹, R², R³ and R⁴ are inthe configurations specified in group 14, e.g., α,β,α,β, β,β,β,β,α,β,β,α or β,β,α,α respectively, (7) 17-16-15-1, 17-16-15-2, 17-16-15-3,17-16-15-4, 17-16-15-5, 17-16-15-5A, 17-16-15-6, 17-16-15-7, 17-16-15-8,17-16-15-8A, 17-16-15-9, 17-16-15-10, 17-16-15-10A, 17-16-15-11,17-16-15-12 and 17-16-15-13, which are the group 15 compounds in group16, and (8) groups 17-16-15-14-1, 17-16-15-14-2, 17-16-15-14-3,17-16-15-14-4, 17-16-15-14-5, 17-16-15-14-5A, 17-16-15-14-6,17-16-15-14-7, 17-16-15-14-8, 17-16-15-14-8A, 17-16-15-14-9,17-16-15-14-10, 17-16-15-14-10A, 17-16-15-14-11, 17-16-15-14-12 and17-16-15-14-13, which are the group 14 compounds in the 16-15 groups.

When R⁵ is —CH₃ in the β-configuration, R⁶ is —H in the β-configurationexemplary compounds include group 17-1 compound 1.1.4.1,3β-hydroxy-16α-fluoro-17α-amino-19-nor-5α-androstane, group 17-1compound 1.1.5.1, 3β-hydroxy-17α-amino-19-nor-5α-androstane, group 17-1compound 1.1.6.1, 3β,16α-dihydroxy-17α-amino-19-nor-5α-androstane. Othercompounds where R⁵ is —CH₃ in the β-configuration and R⁶ is —H in theβ-configuration include (1) group 17-2 compounds 1.1.4.1, 1.1.5.1 and1.1.6.1, i.e., 3β-hydroxy-16α-fluoro-17β-amino-19-nor-5β-androstane,3β-hydroxy-17β-amino-19-nor-5β-androstane, and3β,16α-dihydroxy-17β-amino-19-nor-5β-androstane, (2) group 17-3compounds 1.1.4.1, 1.1.5.1 and 1.1.6.1, i.e.,3β-hydroxy-16α-fluoro-17β-amino-19-norandrost-5-ene,3β-hydroxy-17β-amino-19-norandrost-5-ene, and3β,16α-dihydroxy-17β-amino-19-norandrost-5-ene, (3) group 17-4 compounds1.1.4.1, 1.1.5.1 and 1.1.6.1, i.e.,3β-hydroxy-16α-fluoro-17β-amino-19-norandrost-1,5-diene,3β-hydroxy-17β-amino-19-norandrost-1,5-diene, and3β,16α-dihydroxy-17β-amino-19-norandrost-1,5-diene, (4) group 17-6compounds 1.1.4.1, 1.1.5.1 and 1.1.6.1, i.e.,3β-hydroxy-16α-fluoro-17β-amino-19-norandrost-4-ene,3β-hydroxy-17α-amino-19-norandrost-4-ene, and3β,16α-dihydroxy-17β-amino-19-norandrost-4-ene, (5) group 17-9 compounds1.1.4.1, 1.1.5.1 and 1.1.6.1, i.e.,3β-hydroxy-16-fluoro-17-amino-19-norandrost-5,16-diene,3β-hydroxy-17-amino-19-norandrost-5,16-diene, and3β,16-dihydroxy-17-amino-19-norandrost-5,16-diene, (6) group 17-14-1compounds 1.1.4.1, 1.1.5.1 and 1.1.6.1, where R¹ is in theα-configuration, i.e.,3α-hydroxy-16α-fluoro-17β-amino-19-nor-5α-androstane,3α-hydroxy-17β-amino-19-nor-5α-androstane, and3α,16α-dihydroxy-17β-amino-19-nor-5β-androstane, (7) group 17-14-2compounds 1.1.4.1, 1.1.5.1 and 1.1.6.1, where R¹ is in theα-configuration, i.e.,3α-hydroxy-16α-fluoro-17β-amino-19-nor-5β-androstane,3α-hydroxy-17β-amino-19-nor-5β-androstane, and3α,16α-dihydroxy-17β-amino-19-nor-5β-androstane, (8) group 17-14-3compounds 1.1.4.1, 1.1.5.1 and 1.1.6.1, where R¹ is in theα-configuration, i.e.,3α-hydroxy-16α-fluoro-17β-amino-19-norandrost-5-ene,3α-hydroxy-17β-amino-19-norandrost-5-ene, and3α,16α-dihydroxy-17β-amino-19-norandrost-5-ene, (9) group 17-14-4compounds 1.1.4.1, 1.1.5.1 and 1.1.6.1, where R¹ is in theα-configuration, i.e.,3α-hydroxy-16α-fluoro-17β-amino-19-norandrost-1,5-diene,3α-hydroxy-17β-amino-19-norandrost-1,5-diene, and3α,16α-dihydroxy-17β-amino-19-norandrost-1,5-diene, (10) group 17-14-6compounds 1.1.4.1, 1.1.5.1 and 1.1.6.1, where R¹ is in theα-configuration, i.e.,3α-hydroxy-16α-fluoro-17β-amino-19-norandrost-4-ene,3α-hydroxy-17β-amino-19-norandrost-4-ene, and3α,16α-dihydroxy-17β-amino-19-norandrost-4-ene, and (11) group 17-14-9compounds 1.1.4.1, 1.1.5.1 and 1.1.6.1, i.e.,3α-hydroxy-16-fluoro-17-amino-19-norandrost-5,16-diene,3α-hydroxy-17-amino-19-norandrost-5,16-diene, and3α,16-dihydroxy-17-amino-19-norandrost-5,16-diene. Other exemplaryanalogs of these compounds include those where (1) R⁵ is, e.g., —CH₂OH,—C₂H₅, —CH₂OCH₃ or another moiety described herein for R⁵ or R⁶ and/or(2) similar analogs in other groups such as 17-5A, 17-14-5A, 17-7,17-14-7, 17-11, 17-14-11, 17-13, 17-15-1, 17-15-2, 17-15-3, 17-15-4,17-15-5, 17-15-5A, 17-15-6, 17-15-14-1, 17-15-14-2, 17-15-14-3,17-15-14-4, 17-15-14-5, 17-15-14-5A, 17-16-1, 17-16-2, 17-16-3, 17-16-4,17-16-5, 17-16-5A, 17-16-6, 17-16-14-1, 17-16-14-2, 17-16-14-3,17-16-14-4, 17-16-14-5, 17-16-14-5A, and 17-16-14-6 where, for compoundsin group 14 in group 17 such as 17-14-5A, R¹, R², R³ and R⁴ can be in,e.g., the β,β,α,β, α,β,α,β, β,β,α,α, β,α,α,β, α,β,β,β, α,β,α,α orβ,β,β,β configurations respectively, as described in group 14.

Group 18. This group contains compounds in groups 1-17 above wherein R⁹is not —CH₂— and is another R⁹ moiety defined herein, e.g., —O—, —NH—,—S—, —CH₂—CH₂—, —CHR¹⁰— or —C(R¹⁰)₂— where each R¹⁰ is an independentlychosen moiety described herein, where one or both R¹⁰ are in theβ-configuration and the other R¹⁰ is in the α-configuration. ExemplaryR⁹ include —O—, —C(halogen)₂- such as —CF₂—, —CH(α-optionallysubstituted alkyl), —CH(β-optionally substituted alkyl), —CH(α-OH),—CH(β-OH) or —C(optionally substituted alkyl)₂- such as —C(CH₃)₂— or—C(C₂H₅)(CH₃)—. Each optionally substituted alkyl group can contain 1,2, 3, 4, 5, 6, 7, 8 or more carbon atoms as defined previously. Forgroups that contain a double bond at the 1-2 position such as groups 5and 7, R⁹ can be —N═, but R⁹ will not be —O— or —S— due to improperbonding, i.e., —O═ and —S═ are not present in the steroid ring.Exemplary compounds include those exemplified in the groups above, e.g.,in groups 1, 14 or 17, where R⁹ is, e.g., —O—, —NH—, —N═, —CH(α-F)—,—CH(β-F)—, —CF₂—, —CH(α-optionally substituted alkyl)- or—CH(β-optionally substituted alkyl)-. These compounds include compoundsin group 18-1 through 18-17-16-15-14-13, which collectively are group 18compounds. These include groups 18-1, 18-2, 18-3, 18-4, 18-5, 18-5A,18-6, 18-7, 18-8, 18-8A, 18-9, 18-10, 18-10A, 18-11, 18-12, 18-13, whichare compounds in groups 1 through 13 where R⁹ is not —CH₂—. Group 18compounds also include groups 18-14-1, 18-14-2, 18-14-3, 18-14-4,18-14-5, 18-14-5A, 18-14-6, 18-14-7, 18-14-8, 18-14-8A, 18-14-9,18-14-10, 18-14-10A, 18-14-11, 18-14-12 and 18-14-13, which are group 14compounds in groups 14-1 through 14-13 where R⁹ is not —CH₂—.

Other group 18 compounds include (1) groups 18-15-1, 18-15-2, 18-15-3,18-15-4, 18-15-5, 18-15-5A, 18-15-6, 18-15-7, 18-15-8, 18-15-8A,18-15-9, 18-15-10, 18-15-10A, 18-15-11, 18-15-12 and 18-15-13, which aregroup 15 compounds in groups 15-1 through 15-13 where R⁹ is not —CH₂—,(2) groups 18-16-1, 18-16-2, 18-16-3, 18-16-4, 18-16-5, 18-16-5A,18-16-6, 18-16-7, 18-16-8, 18-16-8A, 18-16-9, 18-16-10, 18-16-10A,18-16-11, 18-16-12 and 18-16-13, which are group 16 compounds in groups16-1 through 16-13 where R⁹ is not —CH₂—, (3) groups 18-17-1, 18-17-2,18-17-3, 18-17-4, 18-17-5, 18-17-5A, 18-17-6, 18-17-7, 18-17-8,18-17-8A, 18-17-9, 18-17-10, 18-17-10A, 18-17-11, 18-17-12 and 18-17-13,which are group 17 compounds in groups 17-1 through 17-13 where R⁹ isnot —CH₂—, (4) groups 18-15-14-1, 18-15-14-2, 18-15-14-3, 18-15-14-4,18-15-14-5, 18-15-14-5A, 18-15-14-6, 18-15-14-7, 18-15-14-8,18-15-14-8A, 18-15-14-9, 18-15-14-10, 18-15-14-10A, 18-15-14-11,18-15-14-12 and 18-15-14-13, which are group 15 compounds in groups15-14-1 through 15-14-13 where R⁹ is not —CH₂—, (5) groups 18-16-14-1,18-16-14-2, 18-16-14-3, 18-16-14-4, 18-16-14-5, 18-16-14-5A, 18-16-14-6,18-16-14-7, 18-16-14-8, 18-16-14-8A, 18-16-14-9, 18-16-14-10,18-16-14-10A, 18-16-14-11, 18-16-14-12 and 18-16-14-13, which are group16 compounds in groups 16-14-1 through 16-14-13 where R⁹ is not —CH₂—,(6) groups 18-17-14-1, 18-17-14-2, 18-17-14-3, 18-17-14-4, 18-17-14-5,18-17-14-5A, 18-17-14-6, 18-17-14-7, 18-17-14-8, 18-17-14-8A,18-17-14-9, 18-17-14-10, 18-17-14-10A, 18-17-14-11, 18-17-14-12,18-17-14-13, which are group 17 compounds in groups 17-14-1 through17-14-13 where R⁹ is not —CH₂—, (7) groups 18-16-15-1, 18-16-15-2,18-16-15-3, 18-16-15-4, 18-16-15-5, 18-16-15-5A, 18-16-15-6, 18-16-15-7,18-16-15-8, 18-16-15-8A, 18-16-15-9, 18-16-15-10, 18-16-15-10A,18-16-15-11, 18-16-15-12, 18-16-15-13, which are group 16 compounds ingroups 16-15-1 through 16-15-13 where R⁹ is not —CH₂—, (8) groups18-17-15-1, 18-17-15-2, 18-17-15-3, 18-17-15-4, 18-17-15-5, 18-17-15-5A,18-17-15-6, 18-17-15-7, 18-17-15-8, 18-17-15-8A, 18-17-15-9,18-17-15-10, 18-17-15-10A, 18-17-15-11, 18-17-15-12, 18-17-15-13, whichare group 17 compounds in groups 17-15-1 through 17-15-13 where R⁹ isnot —CH₂—, (9) groups 18-17-16-1, 18-17-16-2, 18-17-16-3, 18-17-16-4,18-17-16-5, 18-17-16-5A, 18-17-16-6, 18-17-16-7, 18-17-16-8,18-17-16-8A, 18-17-16-9, 18-17-16-10, 18-17-16-10A, 18-17-16-11,18-17-16-12, 18-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13 where R⁹ is not —CH₂—, (10) groups 18-16-15-14-1,18-16-15-14-2, 18-16-15-14-3, 18-16-15-14-4, 18-16-15-14-5,18-16-15-14-5A, 18-16-15-14-6, 18-16-15-14-7, 18-16-15-14-8,18-16-15-14-8A, 18-16-15-14-9, 18-16-15-14-10, 18-16-15-14-10A,18-16-15-14-11, 18-16-15-14-12, 18-16-15-14-13, which are group 16compounds in groups 16-15-14-1 through 16-15-14-13 where R⁹ is not—CH₂—, (11) groups 18-17-15-14-1, 18-17-15-14-2, 18-17-15-14-3,18-17-15-14-4, 18-17-15-14-5, 18-17-15-14-5A, 18-17-15-14-6,18-17-15-14-7, 18-17-15-14-8, 18-17-15-14-8A, 18-17-15-14-9,18-17-15-14-10, 18-17-15-14-10A, 18-17-15-14-11, 18-17-15-14-12,18-17-15-14-13, which are group 17 compounds in groups 17-15-14-1through 17-15-14-13 where R⁹ is not —CH₂—, (12) groups 18-17-16-14-1,18-17-16-14-2, 18-17-16-14-3, 18-17-16-14-4, 18-17-16-14-5,18-17-16-14-5A, 18-17-16-14-6, 18-17-16-14-7, 18-17-16-14-8,18-17-16-14-8A, 18-17-16-14-9, 18-17-16-14-10, 18-17-16-14-10A,18-17-16-14-11, 18-17-16-14-12, 18-17-16-14-13, which are group 17compounds in groups 17-16-14-1 through 17-15-14-13 where R⁹ is not—CH₂—, (13) groups 18-17-16-15-1, 18-17-16-15-2, 18-17-16-15-3,18-17-16-15-4, 18-17-16-15-5, 18-17-16-15-5A, 18-17-16-15-6,18-17-16-15-7, 18-17-16-15-8, 18-17-16-15-8A, 18-17-16-15-9,18-17-16-15-10, 18-17-16-15-10A, 18-17-16-15-11, 18-17-16-15-12 and18-17-16-15-13, which are group 17 compounds in groups 17-16-15-1through 17-16-15-13 where R⁹ is not —CH₂—, and (14) groups18-17-16-15-14-1, 18-17-16-15-14-2, 18-17-16-15-14-3, 18-17-16-15-14-4,18-17-16-15-14-5, 18-17-16-15-14-5A, 18-17-16-15-14-6, 18-17-16-15-14-7,18-17-16-15-14-8, 18-17-16-15-14-8A, 18-17-16-15-14-9,18-17-16-15-14-10, 18-17-16-15-14-10A, 18-17-16-15-14-11,18-17-16-15-14-12 and 18-17-16-15-14-13, which are group 17 compounds ingroups 17-16-15-14-1 through 17-16-15-14-13 where R⁹ is not —CH₂—.

Exemplary group 18 compounds include 2-oxa, 2-thia, 2-aza, 2α-optionallysubstituted alkyl analogs, 2, optionally substituted alkyl and,2-(optionally substituted alkyl)₂, e.g., —C(CH₃)₂— or —C(CH₂OH)₂—,analogs of 3β-hydroxy-17β-aminoandrost-5-ene,3α-hydroxy-17β-aminoandrost-5-ene, 3β-hydroxy-17α-aminoandrost-5-ene,3β,70-dihydroxy-17β-aminoandrost-5-ene,3β-hydroxy-17β-amino-19-norandrost-5-ene,3α-hydroxy-17β-amino-19-norandrost-5-ene,3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-17β-amino-19-norandrost-5-ene and any of the F1Cs or chemicalstructures disclosed herein.

Group 19. This group contains compounds in groups 1-18 above wherein R⁸is not —CH₂— and is another R⁸ moiety defined herein, e.g., —O—, —NH—,—N═, —S— or —C(R¹⁰)₂— where each R¹⁰ is an independently chosen moietydescribed herein, where one R¹⁰ is in the β-configuration and the otherR¹⁰ is in the α-configuration. Exemplary R⁸ include —C(halogen)₂- suchas —CF₂—, —CH(α-optionally substituted alkyl), —CH(, optionallysubstituted alkyl) or —C(optionally substituted alkyl)₂- such as—C(CH₃)₂— or —C(C₂H₅)(CH₃)—. Each optionally substituted alkyl group cancontain 1, 2, 3, 4, 5, 6, 7, 8 or more carbon atoms as definedpreviously. In some embodiments, when one or both R¹⁰ at R³ is —OH, —SH,═O, an ester, a thioester, or another moiety that can give rise to ahydroxyl group by metabolism or hydrolysis, R² and/or R^(10D) is not —H.

These compounds include compounds in group 19-1 through19-18-17-16-15-14-13, which collectively are group 19 compounds. Theseinclude groups 19-1, 19-2, 19-3, 19-4, 19-5, 19-5A, 19-6, 19-7, 19-8,19-8A, 19-9, 19-10, 19-10A, 19-11, 19-12, 19-13, which are compounds ingroups 1 through 13 where R⁸ is not —CH₂—. Group 19 compounds alsoinclude groups 19-14-1, 19-14-2, 19-14-3, 19-14-4, 19-14-5, 19-14-5A,19-14-6, 19-14-7, 19-14-8, 19-14-8A, 19-14-9, 19-14-10, 19-14-10A,19-14-11, 19-14-12 and 19-14-13, which are group 14 compounds in groups14-1 through 14-13 where R⁸ is not —CH₂—.

Other group 19 compounds include (1) groups 19-15-1, 19-15-2, 19-15-3,19-15-4, 19-15-5, 19-15-5A, 19-15-6, 19-15-7, 19-15-8, 19-15-8A,19-15-9, 19-15-10, 19-15-10A, 19-15-11, 19-15-12 and 19-15-13, which aregroup 15 compounds in groups 15-1 through 15-13 where R⁸ is not —CH₂—,(2) groups 19-16-1, 19-16-2, 19-16-3, 19-16-4, 19-16-5, 19-16-5A,19-16-6, 19-16-7, 19-16-8, 19-16-8A, 19-16-9, 19-16-10, 19-16-10A,19-16-11, 19-16-12 and 19-16-13, which are group 16 compounds in groups16-1 through 16-13 where R⁸ is not —CH₂—, (3) groups 19-17-1, 19-17-2,19-17-3, 19-17-4, 19-17-5, 19-17-5A, 19-17-6, 19-17-7, 19-17-8,19-17-8A, 19-17-9, 19-17-10, 19-17-10A, 19-17-11, 19-17-12 and 19-17-13,which are group 17 compounds in groups 17-1 through 17-13 where R⁸ isnot —CH₂—, (4) groups 19-15-14-1, 19-15-14-2, 19-15-14-3, 19-15-14-4,19-15-14-5, 19-15-14-5A, 19-15-14-6, 19-15-14-7, 19-15-14-8,19-15-14-8A, 19-15-14-9, 19-15-14-10, 19-15-14-10A, 19-15-14-11,19-15-14-12 and 19-15-14-13, which are group 15 compounds in groups15-14-1 through 15-14-13 where R⁸ is not —CH₂—, (5) groups 19-16-14-1,19-16-14-2, 19-16-14-3, 19-16-14-4, 19-16-14-5, 19-16-14-5A, 19-16-14-6,19-16-14-7, 19-16-14-8, 19-16-14-8A, 19-16-14-9, 19-16-14-10,19-16-14-10A, 19-16-14-11, 19-16-14-12 and 19-16-14-13, which are group16 compounds in groups 16-14-1 through 16-14-13 where R⁸ is not —CH₂—,(6) groups 19-17-14-1, 19-17-14-2, 19-17-14-3, 19-17-14-4, 19-17-14-5,19-17-14-5A, 19-17-14-6, 19-17-14-7, 19-17-14-8, 19-17-14-8A,19-17-14-9, 19-17-14-10, 19-17-14-10A, 19-17-14-11, 19-17-14-12,19-17-14-13, which are group 17 compounds in groups 17-14-1 through17-14-13 where R⁸ is not —CH₂—, (7) groups 19-16-15-1, 19-16-15-2,19-16-15-3, 19-16-15-4, 19-16-15-5, 19-16-15-5A, 19-16-15-6, 19-16-15-7,19-16-15-8, 19-16-15-8A, 19-16-15-9, 19-16-15-10, 19-16-15-10A,19-16-15-11, 19-16-15-12, 19-16-15-13, which are group 16 compounds ingroups 16-15-1 through 16-15-13 where R⁸ is not —CH₂—, (8) groups19-17-15-1, 19-17-15-2, 19-17-15-3, 19-17-15-4, 19-17-15-5, 19-17-15-5A,19-17-15-6, 19-17-15-7, 19-17-15-8, 19-17-15-8A, 19-17-15-9,19-17-15-10, 19-17-15-10A, 19-17-15-11, 19-17-15-12, 19-17-15-13, whichare group 17 compounds in groups 17-15-1 through 17-15-13 where R⁸ isnot —CH₂—, (9) groups 19-17-16-1, 19-17-16-2, 19-17-16-3, 19-17-16-4,19-17-16-5, 19-17-16-5A, 19-17-16-6, 19-17-16-7, 19-17-16-8,19-17-16-8A, 19-17-16-9, 19-17-16-10, 19-17-16-10A, 19-17-16-11,19-17-16-12, 19-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13 where R⁸ is not —CH₂—, (10) groups 19-16-15-14-1,19-16-15-14-2, 19-16-15-14-3, 19-16-15-14-4, 19-16-15-14-5,19-16-15-14-5A, 19-16-15-14-6, 19-16-15-14-7, 19-16-15-14-8,19-16-15-14-8A, 19-16-15-14-9, 19-16-15-14-10, 19-16-15-14-10A,19-16-15-14-11, 19-16-15-14-12, 19-16-15-14-13, which are group 16compounds in groups 16-15-14-1 through 16-15-14-13 where R⁸ is not—CH₂—, (11) groups 19-17-15-14-1, 19-17-15-14-2, 19-17-15-14-3,19-17-15-14-4, 19-17-15-14-5, 19-17-15-14-5A, 19-17-15-14-6,19-17-15-14-7, 19-17-15-14-8, 19-17-15-14-8A, 19-17-15-14-9,19-17-15-14-10, 19-17-15-14-10A, 19-17-15-14-11, 19-17-15-14-12,19-17-15-14-13, which are group 17 compounds in groups 17-15-14-1through 17-15-14-13 where R⁸ is not —CH₂—, (12) groups 19-17-16-14-1,19-17-16-14-2, 19-17-16-14-3, 19-17-16-14-4, 19-17-16-14-5,19-17-16-14-5A, 19-17-16-14-6, 19-17-16-14-7, 19-17-16-14-8,19-17-16-14-8A, 19-17-16-14-9, 19-17-16-14-10, 19-17-16-14-10A,19-17-16-14-11, 19-17-16-14-12, 19-17-16-14-13, which are group 17compounds in groups 17-16-14-1 through 17-15-14-13 where R⁸ is not—CH₂—, (13) groups 19-17-16-15-1, 19-17-16-15-2, 19-17-16-15-3,19-17-16-15-4, 19-17-16-15-5, 19-17-16-15-5A, 19-17-16-15-6,19-17-16-15-7, 19-17-16-15-8, 19-17-16-15-8A, 19-17-16-15-9,19-17-16-15-10, 19-17-16-15-10A, 19-17-16-15-11, 19-17-16-15-12 and19-17-16-15-13, which are group 17 compounds in groups 17-16-15-1through 17-16-15-13 where R⁸ is not —CH₂—, (14) groups 19-17-16-15-14-1,19-17-16-15-14-2, 19-17-16-15-14-3, 19-17-16-15-14-4, 19-17-16-15-14-5,19-17-16-15-14-5A, 19-17-16-15-14-6, 19-17-16-15-14-7, 19-17-16-15-14-8,19-17-16-15-14-8A, 19-17-16-15-14-9, 19-17-16-15-14-10,19-17-16-15-14-10A, 19-17-16-15-14-11, 19-17-16-15-14-12 and19-17-16-15-14-13, which are group 17 compounds in groups 17-16-15-14-1through 17-16-15-14-13 where R⁸ is not —CH₂— and (15) all of thecompounds and/or groups described in group 18 where R⁸ is not —CH₂—.

Exemplary group 19 compounds include 11-oxa, 11-thia, 11-aza,11α-optionally substituted alkyl analogs, 11β-optionally substitutedalkyl, 11-(optionally substituted alkyl)₂, e.g., —C(CH₃)₂— or—C(CH₂OH)₂—, analogs of 3β-hydroxy-17β-aminoandrost-5-ene,2-oxa-3β-hydroxy-17β-aminoandrost-5-ene,3α-hydroxy-17β-aminoandrost-5-ene, 3β-hydroxy-17α-aminoandrost-5-ene,3β,7β-dihydroxy-17β-aminoandrost-5-ene,3β-hydroxy-17β-amino-19-norandrost-5-ene,3α-hydroxy-17β-amino-19-norandrost-5-ene,3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-17β-amino-19-norandrost-5-ene and any of the F1Cs or chemicalstructures disclosed herein.

Group 20. This group contains compounds in groups 1-19 above wherein R⁷is not —CH₂— and is another R⁷ moiety defined herein, e.g., —O—, —NH—,—S— or —C(R¹⁰)₂— where each R¹⁰ is an independently chosen moiety asdefined herein. Exemplary R⁷ include —C(halogen)₂- such as —CF₂—,—CH(α-OH), —CH(β-OH) or —C(optionally substituted alkyl)₂-such as—C(CH₃)₂— or —C(C₂H₅)(CH₃)—. Each optionally substituted alkyl group cancontain 1, 2, 3, 4, 5, 6, 7, 8 or more carbon atoms as definedpreviously.

These compounds include compounds in group 20-1 through20-19-18-17-16-15-14-13, which collectively are group 19 compounds.These include groups 20-1, 20-2, 20-3, 20-4, 20-5, 20-5A, 20-6, 20-7,20-8, 20-8A, 20-9, 20-10, 20-10A, 20-11, 20-12, 20-13, which arecompounds in groups 1 through 13 where R⁷ is not —CH₂—. Group 20compounds also include groups 20-14-1, 20-14-2, 20-14-3, 20-14-4,20-14-5, 20-14-5A, 20-14-6, 20-14-7, 20-14-8, 20-14-8A, 20-14-9,20-14-10, 20-14-10A, 20-14-11, 20-14-12 and 20-14-13, which are group 14compounds in groups 14-1 through 14-13 where R⁷ is not —CH₂—.

Other group 20 compounds include (1) groups 20-15-1, 20-15-2, 20-15-3,20-15-4, 20-15-5, 20-15-5A, 20-15-6, 20-15-7, 20-15-8, 20-15-8A,20-15-9, 20-15-10, 20-15-10A, 20-15-11, 20-15-12 and 20-15-13, which aregroup 15 compounds in groups 15-1 through 15-13 where R⁷ is not —CH₂—,(2) groups 20-16-1, 20-16-2, 20-16-3, 20-16-4, 20-16-5, 20-16-5A,20-16-6, 20-16-7, 20-16-8, 20-16-8A, 20-16-9, 20-16-10, 20-16-10A,20-16-11, 20-16-12 and 20-16-13, which are group 16 compounds in groups16-1 through 16-13 where R⁷ is not —CH₂—, (3) groups 20-17-1, 20-17-2,20-17-3, 20-17-4, 20-17-5, 20-17-5A, 20-17-6, 20-17-7, 20-17-8,20-17-8A, 20-17-9, 20-17-10, 20-17-10A, 20-17-11, 20-17-12 and 20-17-13,which are group 17 compounds in groups 17-1 through 17-13 where R⁷ isnot —CH₂—, (4) groups 20-15-14-1, 20-15-14-2, 20-15-14-3, 20-15-14-4,20-15-14-5, 20-15-14-5A, 20-15-14-6, 20-15-14-7, 20-15-14-8,20-15-14-8A, 20-15-14-9, 20-15-14-10, 20-15-14-10A, 20-15-14-11,20-15-14-12 and 20-15-14-13, which are group 15 compounds in groups15-14-1 through 15-14-13 where R⁷ is not —CH₂—, (5) groups 20-16-14-1,20-16-14-2, 20-16-14-3, 20-16-14-4, 20-16-14-5, 20-16-14-5A, 20-16-14-6,20-16-14-7, 20-16-14-8, 20-16-14-8A, 20-16-14-9, 20-16-14-10,20-16-14-10A, 20-16-14-11, 20-16-14-12 and 20-16-14-13, which are group16 compounds in groups 16-14-1 through 16-14-13 where R⁷ is not —CH₂—,(6) groups 20-17-14-1, 20-17-14-2, 20-17-14-3, 20-17-14-4, 20-17-14-5,20-17-14-5A, 20-17-14-6, 20-17-14-7, 20-17-14-8, 20-17-14-8A,20-17-14-9, 20-17-14-10, 20-17-14-10A, 20-17-14-11, 20-17-14-12,20-17-14-13, which are group 17 compounds in groups 17-14-1 through17-14-13 where R⁷ is not —CH₂—, (7) groups 20-16-15-1, 20-16-15-2,20-16-15-3, 20-16-15-4, 20-16-15-5, 20-16-15-5A, 20-16-15-6, 20-16-15-7,20-16-15-8, 20-16-15-8A, 20-16-15-9, 20-16-15-10, 20-16-15-10A,20-16-15-11, 20-16-15-12, 20-16-15-13, which are group 16 compounds ingroups 16-15-1 through 16-15-13 where R⁷ is not —CH₂—, (8) groups20-17-15-1, 20-17-15-2, 20-17-15-3, 20-17-15-4, 20-17-15-5, 20-17-15-5A,20-17-15-6, 20-17-15-7, 20-17-15-8, 20-17-15-8A, 20-17-15-9,20-17-15-10, 20-17-15-10A, 20-17-15-11, 20-17-15-12, 20-17-15-13, whichare group 17 compounds in groups 17-15-1 through 17-15-13 where R⁷ isnot —CH₂—, (9) groups 20-17-16-1, 20-17-16-2, 20-17-16-3, 20-17-16-4,20-17-16-5, 20-17-16-5A, 20-17-16-6, 20-17-16-7, 20-17-16-8,20-17-16-8A, 20-17-16-9, 20-17-16-10, 20-17-16-10A, 20-17-16-11,20-17-16-12, 20-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13 where R⁷ is not —CH₂—, (10) groups 20-16-15-14-1,20-16-15-14-2, 20-16-15-14-3, 20-16-15-14-4, 20-16-15-14-5,20-16-15-14-5A, 20-16-15-14-6, 20-16-15-14-7, 20-16-15-14-8,20-16-15-14-8A, 20-16-15-14-9, 20-16-15-14-10, 20-16-15-14-10A,20-16-15-14-11, 20-16-15-14-12, 20-16-15-14-13, which are group 16compounds in groups 16-15-14-1 through 16-15-14-13 where R⁷ is not—CH₂—, (11) groups 20-17-15-14-1, 20-17-15-14-2, 20-17-15-14-3,20-17-15-14-4, 20-17-15-14-5, 20-17-15-14-5A, 20-17-15-14-6,20-17-15-14-7, 20-17-15-14-8, 20-17-15-14-8A, 20-17-15-14-9,20-17-15-14-10, 20-17-15-14-10A, 20-17-15-14-11, 20-17-15-14-12,20-17-15-14-13, which are group 17 compounds in groups 17-15-14-1through 17-15-14-13 where R⁷ is not —CH₂—, (12) groups 20-17-16-14-1,20-17-16-14-2, 20-17-16-14-3, 20-17-16-14-4, 20-17-16-14-5,20-17-16-14-5A, 20-17-16-14-6, 20-17-16-14-7, 20-17-16-14-8,20-17-16-14-8A, 20-17-16-14-9, 20-17-16-14-10, 20-17-16-14-10A,20-17-16-14-11, 20-17-16-14-12, 20-17-16-14-13, which are group 17compounds in groups 17-16-14-1 through 17-15-14-13 where R⁷ is not—CH₂—, (13) groups 20-17-16-15-1, 20-17-16-15-2, 20-17-16-15-3,20-17-16-15-4, 20-17-16-15-5, 20-17-16-15-5A, 20-17-16-15-6,20-17-16-15-7, 20-17-16-15-8, 20-17-16-15-8A, 20-17-16-15-9,20-17-16-15-10, 20-17-16-15-10A, 20-17-16-15-11, 20-17-16-15-12 and20-17-16-15-13, which are group 17 compounds in groups 17-16-15-1through 17-16-15-13 where R⁷ is not —CH₂—, (14) groups 20-17-16-15-14-1,20-17-16-15-14-2, 20-17-16-15-14-3, 20-17-16-15-14-4, 20-17-16-15-14-5,20-17-16-15-14-5A, 20-17-16-15-14-6, 20-17-16-15-14-7, 20-17-16-15-14-8,20-17-16-15-14-8A, 20-17-16-15-14-9, 20-17-16-15-14-10,20-17-16-15-14-10A, 20-17-16-15-14-11, 20-17-16-15-14-12 and20-17-16-15-14-13, which are group 17 compounds in groups 17-16-15-14-1through 17-16-15-14-13 where R⁷ is not —CH₂—, (15) all of the compoundsand/or groups described in group 18 where R⁷ is not —CH₂— and (16) allof the compounds and/or groups described in group 19 where R⁷ is not—CH₂—.

Exemplary group 20 compounds include 15-oxa, 15-thia, 15-aza,11α-optionally substituted alkyl analogs, 11β-optionally substitutedalkyl, 15-(optionally substituted alkyl)₂, e.g., —C(CH₃)₂— or—C(CH₂OH)₂—, analogs of 3β-hydroxy-17β-aminoandrost-5-ene,2-oxa-3β-hydroxy-17β-aminoandrost-5-ene,3α-hydroxy-17β-aminoandrost-5-ene, 3β-hydroxy-17α-aminoandrost-5-ene,3β,7β-dihydroxy-17β-aminoandrost-5-ene,3β-hydroxy-17β-amino-19-norandrost-5-ene,3α-hydroxy-17β-amino-19-norandrost-5-ene,3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-17β-amino-19-norandrost-5-ene and any of the F1Cs or chemicalstructures disclosed herein.

Group 21. This group contains compounds in groups 1-20 above where R⁴substituents 1-10 listed in Table A are replaced with the followinggroups: 1-optionally substituted amine, 2-optionally substituted amide,3-optionally substituted oxime, 4 -optionally substituted alkyl,5-optionally substituted alkenyl, 6-optionally substituted alkynyl,7-optionally substituted aryl, 8-optionally substituted heterocycle,9-ether, e.g., methoxy, ethoxy or methoxymethyl and 10-ester, e.g.,acetate, propionate, n-butyrate, i-butyrate, t-butyrate, enanthate ortrifluoroacetate. Any of these groups can be a moiety defined herein forthat group. Thus, for Table A substituent 1, optionally substitutedamine, the R⁴ group includes any optionally substituted amine moietiesdescribed herein such as —NH₂, —NH₃ ⁺Cl⁻, —NH₃ ⁺Br⁻, —NH₃ ⁺I⁻,optionally substituted alkylamine, di-optionally substituted alkylamine,—NHR^(PR), —N(R^(PR))₂, —NH—CH₃, —N(CH₃)₂, —N(C₂H₅)₂, —N(n-propyl)₂,—N(i-propyl)₂, —N(n-butyl)₂, —N(t-butyl)₂, —NH—C₁₋₄ alkyl, —NH—C₁₋₄hydroxyalkyl, —NH—C₁₋₄ fluoroalkyl, —NH—C₅₋₈ alkyl, —NH—C₅₋₈hydroxyalkyl, —NH—C₅₋₈ fluoroalkyl, —NH—C₅₋₈ (halo)_(n)-alkyl where n is1, 2, 3, 4, 5, 6, 7 or 8 and the halogens are the same or different,—NH—CH₂—CH₂—C(O)—OH or a salt, —NH—CH₂—CH₂—C(O)—OCH₃,—NH—CH₂—CH₂—O—C(O)—OCH₃ and —NH—CH₂—CH₂—O—CH₃, where R^(PR) areindependently selected protecting groups and any alkyl group contains 1,2, 3, 4, 5, 6, 7, 8, 9, 10 or more carbon atoms and is optionallysubstituted as described herein. Similarly, optionally substituted amideincludes moieties such as —C(O)—NH₂, —NH—C(O)—CH₃, —NH—C(O)—CF₃,—NH—C(O)—C₂H₅, —C(O)—NH—C(CH₃)₃ and —C(O)—NH₂, which are describedherein. Other R⁴ moieties include ═N—OCH₃, ═N—OC₂H₅, ═N—OC₃H₇ and═N—O-optionally substituted alkyl, —NH₂, —NHCH₃, —N(CH₃)₂, —NHC₂H₅,—N(C₂H₅)₂, —NHC₃H₇, —N(C₃H₇)₂, —NHC₄H₉, —N(C₄H₉)₂, —NH-optionallysubstituted alkyl, —N(optionally substituted alkyl)₂, —NH—C₆H₅,—N(C₆H₅)₂, —NH-optionally substituted monosaccharide —NH-optionallysubstituted oligosaccharide, —NHC(O)-optionally substituted alkyl,—N(CH₃)—C(O)-optionally substituted alkyl, —N(C₂H₅)—C(O)-optionallysubstituted alkyl, —N(C₃H₇)—C(O)-optionally substituted alkyl,—N(C₄H₉)—C(O)-optionally substituted alkyl, —N(C₆H₅)—C(O)-optionallysubstituted alkyl, —NH—C(O)-optionally substituted monosaccharide and—NH—C(O)-optionally substituted oligosaccharide, where alkyl or phenylgroups are the same or different and are optionally substituted asdescribed herein.

These compounds include compounds in group 21-1 through21-20-19-18-17-16-15-14-13, which collectively are group 21 compounds.These include groups 21-1, 21-2, 21-3, 21-4, 21-5, 21-5A, 21-6, 21-7,21-8, 21-8A, 21-9, 21-10, 21-10A, 21-11, 21-12, 21-13, which arecompounds in groups 1 through 13 where R⁴ substituents 1-10 in Table Aare replaced with the moieties given in this group. Group 21 compoundsalso include groups 21-14-1, 21-14-2, 21-14-3, 21-14-4, 21-14-5,21-14-5A, 21-14-6, 21-14-7, 21-14-8, 21-14-8A, 21-14-9, 21-14-10,21-14-10A, 21-14-11, 21-14-12 and 21-14-13, which are group 14 compoundsin groups 14-1 through 14-13 where R⁴ substituents 1-10 in Table A arereplaced with the moieties given in this group.

Other group 21 compounds include (1) groups 21-15-1, 21-15-2, 21-15-3,21-15-4, 21-15-5, 21-15-5A, 21-15-6, 21-15-7, 21-15-8, 21-15-8A,21-15-9, 21-15-10, 21-15-10A, 21-15-11, 21-15-12 and 21-15-13, which aregroup 15 compounds in groups 15-1 through 15-13, (2) groups 21-16-1,21-16-2, 21-16-3, 21-16-4, 21-16-5, 21-16-5A, 21-16-6, 21-16-7, 21-16-8,21-16-8A, 21-16-9, 21-16-10, 21-16-10A, 21-16-11, 21-16-12 and 21-16-13,which are group 16 compounds in groups 16-1 through 16-13, (3) groups21-17-1, 21-17-2, 21-17-3, 21-17-4, 21-17-5, 21-17-5A, 21-17-6, 21-17-7,21-17-8, 21-17-8A, 21-17-9, 21-17-10, 21-17-10A, 21-17-11, 21-17-12 and21-17-13, which are group 17 compounds in groups 17-1 through 17-13, (4)groups 21-15-14-1, 21-15-14-2, 21-15-14-3, 21-15-14-4, 21-15-14-5,21-15-14-5A, 21-15-14-6, 21-15-14-7, 21-15-14-8, 21-15-14-8A,21-15-14-9, 21-15-14-10, 21-15-14-10A, 21-15-14-11, 21-15-14-12 and21-15-14-13, which are group 15 compounds in groups 15-14-1 through15-14-13, (5) groups 21-16-14-1, 21-16-14-2, 21-16-14-3, 21-16-14-4,21-16-14-5, 21-16-14-5A, 21-16-14-6, 21-16-14-7, 21-16-14-8,21-16-14-8A, 21-16-14-9, 21-16-14-10, 21-16-14-10A, 21-16-14-11,21-16-14-12 and 21-16-14-13, which are group 16 compounds in groups16-14-1 through 16-14-13, (6) groups 21-17-14-1, 21-17-14-2, 21-17-14-3,21-17-14-4, 21-17-14-5, 21-17-14-5A, 21-17-14-6, 21-17-14-7, 21-17-14-8,21-17-14-8A, 21-17-14-9, 21-17-14-10, 21-17-14-10A, 21-17-14-11,21-17-14-12, 21-17-14-13, which are group 17 compounds in groups 17-14-1through 17-14-13, (7) groups 21-16-15-1, 21-16-15-2, 21-16-15-3,21-16-15-4, 21-16-15-5, 21-16-15-5A, 21-16-15-6, 21-16-15-7, 21-16-15-8,21-16-15-8A, 21-16-15-9, 21-16-15-10, 21-16-15-10A, 21-16-15-11,21-16-15-12, 21-16-15-13, which are group 16 compounds in groups 16-15-1through 16-15-13, (8) groups 21-17-15-1, 21-17-15-2, 21-17-15-3,21-17-15-4, 21-17-15-5, 21-17-15-5A, 21-17-15-6, 21-17-15-7, 21-17-15-8,21-17-15-8A, 21-17-15-9, 21-17-15-10, 21-17-15-10A, 21-17-15-11,21-17-15-12, 21-17-15-13, which are group 17 compounds in groups 17-15-1through 17-15-13, (9) groups 21-17-16-1, 21-17-16-2, 21-17-16-3,21-17-16-4, 21-17-16-5, 21-17-16-5A, 21-17-16-6, 21-17-16-7, 21-17-16-8,21-17-16-8A, 21-17-16-9, 21-17-16-10, 21-17-16-10A, 21-17-16-11,21-17-16-12, 21-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13, (10) groups 21-16-15-14-1, 21-16-15-14-2,21-16-15-14-3, 21-16-15-14-4, 21-16-15-14-5, 21-16-15-14-5A,21-16-15-14-6, 21-16-15-14-7, 21-16-15-14-8, 21-16-15-14-8A,21-16-15-14-9, 21-16-15-14-10, 21-16-15-14-10A, 21-16-15-14-11,21-16-15-14-12, 21-16-15-14-13, which are group 16 compounds in groups16-15-14-1 through 16-15-14-13, (11) groups 21-17-15-14-1,21-17-15-14-2, 21-17-15-14-3, 21-17-15-14-4, 21-17-15-14-5,21-17-15-14-5A, 21-17-15-14-6, 21-17-15-14-7, 21-17-15-14-8,21-17-15-14-8A, 21-17-15-14-9, 21-17-15-14-10, 21-17-15-14-10A,21-17-15-14-11, 21-17-15-14-12, 21-17-15-14-13, which are group 17compounds in groups 17-15-14-1 through 17-15-14-13, (12) groups21-17-16-14-1, 21-17-16-14-2, 21-17-16-14-3, 21-17-16-14-4,21-17-16-14-5, 21-17-16-14-5A, 21-17-16-14-6, 21-17-16-14-7,21-17-16-14-8, 21-17-16-14-8A, 21-17-16-14-9, 21-17-16-14-10,21-17-16-14-10A, 21-17-16-14-11, 21-17-16-14-12, 21-17-16-14-13, whichare group 17 compounds in groups 17-16-14-1 through 17-15-14-13, (13)groups 21-17-16-15-1, 21-17-16-15-2, 21-17-16-15-3, 21-17-16-15-4,21-17-16-15-5, 21-17-16-15-5A, 21-17-16-15-6, 21-17-16-15-7,21-17-16-15-8, 21-17-16-15-8A, 21-17-16-15-9, 21-17-16-15-10,21-17-16-15-10A, 21-17-16-15-11, 21-17-16-15-12 and 21-17-16-15-13,which are group 17 compounds in groups 17-16-15-1 through 17-16-15-13,(14) groups 21-17-16-15-14-1, 21-17-16-15-14-2, 21-17-16-15-14-3,21-17-16-15-14-4, 21-17-16-15-14-5, 21-17-16-15-14-5A, 21-17-16-15-14-6,21-17-16-15-14-7, 21-17-16-15-14-8, 21-17-16-15-14-8A, 21-17-16-15-14-9,21-17-16-15-14-10, 21-17-16-15-14-10A, 21-17-16-15-14-11,21-17-16-15-14-12 and 21-17-16-15-14-13, which are group 17 compounds ingroups 17-16-15-14-1 through 17-16-15-14-13, (15) all of the compoundsand/or groups described in group 18, (16) all of the compounds and/orgroups described in group 19 and (17) all of the compounds and/or groupsdescribed in group 20.

Exemplary group 21 compounds include3β-hydroxy-17β-methylaminoandrost-5-ene,3β-hydroxy-17β-methylamino-5α-androstane,3α-hydroxy-17β-methylamino-5α-androstane,3β-hydroxy-17β-methylamino-5β-androstane,3β-hydroxy-17β-methylamino-5β-androst-1-ene,3α-hydroxy-17β-methylamino-5β-androst-1-ene,3β-hydroxy-17α-methylamino-5β-androst-1-ene,3β-hydroxy-17β-methylamino-5α-androst-1-ene,3β-hydroxy-17β-methylamino-5α, 14β-androst-1-ene,3β-hydroxy-17β-methylamino-5α, 14β-androstane,3β-hydroxy-17β-hydroxyaminoandrost-5-ene,3β-hydroxy-17β-methylaminoandrost-1,5-diene,3β-hydroxy-17β-methylaminoandrost-4-ene,2-oxa-3β-hydroxy-17β-methylaminoandrost-5-ene,3α-hydroxy-17β-methylaminoandrost-5-ene,3β-hydroxy-17α-methylaminoandrost-5-ene,3β,7β-dihydroxy-17β-ethylaminoandrost-5-ene,3β-hydroxy-17β-methylamino-19-norandrost-5-ene,3α-hydroxy-17β-methylamino-19-norandrost-5-ene,3β-hydroxy-16α-fluoro-17β-methylaminoandrost-5-ene,3β-hydroxy-16α-fluoro-17β-methylaminoandrost-1,4-diene,3β-hydroxy-17β-dimethylamino-19-norandrost-5-ene, analogs of any ofthese compounds where the methyl or ethyl group is substituted, e.g.,with —OH, halogen or —C(O)OR^(PR)

Group 22. This group contains compounds in groups 1-20 above where R⁴substituents 1-10 listed in Table A are replaced with the followinggroups: 1-acyl, 2-thioester, 3-thioether, 4-thioacyl, 5-epoxide,6-optionally substituted cyclopropyl, 7 —O—Si(C1-C6 alkyl)₃,8-phosphate, 9-phosphate ester, and 10-phosphate ether. Any of thesegroups can be a moiety defined herein for that group. Thus, for Table Asubstituent 1, acyl, the R⁴ group includes moieties such as —C(O)CH₃,—C(O)C₂H₅, —C(O)CH₂OH, —C(O)CH₂-halogen and —C(O)-optionally substitutedalkyl. Similarly, thioester includes moieties such as —C(O)—SCH₃,—C(O)—SC₂H₅, —S—C(O)-optionally substituted alkyl and —C(O)—S-optionallysubstituted alkyl. The epoxide and optionally substituted cyclopropylmoieties for substituents 5 and 6 respectively can be at the 16-17positions or at the 17-18 positions. For any ionizable moiety in thisgroup, e.g., phosphate, or any other group disclosed herein, e.g.,optionally substituted carboxyl in group 23 below, the moiety can bepresent as the free moiety, e.g., sulfate, phosphate, carboxyl or amine,or it may be present as a salt with a suitable counter ion, e.g., anyion disclosed herein such as F⁻, Cl⁻, I⁻, Ca⁺⁺, NH₄ ⁺, Na⁺ or K⁺.

These compounds include compounds in group 22-1 through22-20-19-18-17-16-15-14-13, which collectively are group 22 compounds.These include groups 22-1, 22-2, 22-3, 22-4, 22-5, 22-5A, 22-6, 22-7,22-8, 22-8A, 22-9, 22-10, 22-10A, 22-11, 22-12, 22-13, which arecompounds in groups 1 through 13 where R⁴ substituents 1-10 in Table Aare replaced with the moieties given in this group. Group 22 compoundsalso include groups 22-14-1, 22-14-2, 22-14-3, 22-14-4, 22-14-5,22-14-5A, 22-14-6, 22-14-7, 22-14-8, 22-14-8A, 22-14-9, 22-14-10,22-14-10A, 22-14-11, 22-14-12 and 22-14-13, which are group 14 compoundsin groups 14-1 through 14-13 where R⁴ substituents 1-10 in Table A arereplaced with the moieties given in this group.

Other group 22 compounds include (1) groups 22-15-1, 22-15-2, 22-15-3,22-15-4, 22-15-5, 22-15-5A, 22-15-6, 22-15-7, 22-15-8, 22-15-8A,22-15-9, 22-15-10, 22-15-10A, 22-15-11, 22-15-12 and 22-15-13, which aregroup 15 compounds in groups 15-1 through 15-13, (2) groups 22-16-1,22-16-2, 22-16-3, 22-16-4, 22-16-5, 22-16-5A, 22-16-6, 22-16-7, 22-16-8,22-16-8A, 22-16-9, 22-16-10, 22-16-10A, 22-16-11, 22-16-12 and 22-16-13,which are group 16 compounds in groups 16-1 through 16-13, (3) groups22-17-1, 22-17-2, 22-17-3, 22-17-4, 22-17-5, 22-17-5A, 22-17-6, 22-17-7,22-17-8, 22-17-8A, 22-17-9, 22-17-10, 22-17-10A, 22-17-11, 22-17-12 and22-17-13, which are group 17 compounds in groups 17-1 through 17-13, (4)groups 22-15-14-1, 22-15-14-2, 22-15-14-3, 22-15-14-4, 22-15-14-5,22-15-14-5A, 22-15-14-6, 22-15-14-7, 22-15-14-8, 22-15-14-8A,22-15-14-9, 22-15-14-10, 22-15-14-10A, 22-15-14-11, 22-15-14-12 and22-15-14-13, which are group 15 compounds in groups 15-14-1 through15-14-13, (5) groups 22-16-14-1, 22-16-14-2, 22-16-14-3, 22-16-14-4,22-16-14-5, 22-16-14-5A, 22-16-14-6, 22-16-14-7, 22-16-14-8,22-16-14-8A, 22-16-14-9, 22-16-14-10, 22-16-14-10A, 22-16-14-11,22-16-14-12 and 22-16-14-13, which are group 16 compounds in groups16-14-1 through 16-14-13, (6) groups 22-17-14-1, 22-17-14-2, 22-17-14-3,22-17-14-4, 22-17-14-5, 22-17-14-5A, 22-17-14-6, 22-17-14-7, 22-17-14-8,22-17-14-8A, 22-17-14-9, 22-17-14-10, 22-17-14-10A, 22-17-14-11,22-17-14-12, 22-17-14-13, which are group 17 compounds in groups 17-14-1through 17-14-13, (7) groups 22-16-15-1, 22-16-15-2, 22-16-15-3,22-16-15-4, 22-16-15-5, 22-16-15-5A, 22-16-15-6, 22-16-15-7, 22-16-15-8,22-16-15-8A, 22-16-15-9, 22-16-15-10, 22-16-15-10A, 22-16-15-11,22-16-15-12, 22-16-15-13, which are group 16 compounds in groups 16-15-1through 16-15-13, (8) groups 22-17-15-1, 22-17-15-2, 22-17-15-3,22-17-15-4, 22-17-15-5, 22-17-15-5A, 22-17-15-6, 22-17-15-7, 22-17-15-8,22-17-15-8A, 22-17-15-9, 22-17-15-10, 22-17-15-10A, 22-17-15-11,22-17-15-12, 22-17-15-13, which are group 17 compounds in groups 17-15-1through 17-15-13, (9) groups 22-17-16-1, 22-17-16-2, 22-17-16-3,22-17-16-4, 22-17-16-5, 22-17-16-5A, 22-17-16-6, 22-17-16-7, 22-17-16-8,22-17-16-8A, 22-17-16-9, 22-17-16-10, 22-17-16-10A, 22-17-16-11,22-17-16-12, 22-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13, (10) groups 22-16-15-14-1, 22-16-15-14-2,22-16-15-14-3, 22-16-15-14-4, 22-16-15-14-5, 22-16-15-14-5A,22-16-15-14-6, 22-16-15-14-7, 22-16-15-14-8, 22-16-15-14-8A,22-16-15-14-9, 22-16-15-14-10, 22-16-15-14-10A, 22-16-15-14-11,22-16-15-14-12, 22-16-15-14-13, which are group 16 compounds in groups16-15-14-1 through 16-15-14-13, (11) groups 22-17-15-14-1,22-17-15-14-2, 22-17-15-14-3, 22-17-15-14-4, 22-17-15-14-5,22-17-15-14-5A, 22-17-15-14-6, 22-17-15-14-7, 22-17-15-14-8,22-17-15-14-8A, 22-17-15-14-9, 22-17-15-14-10, 22-17-15-14-10A,22-17-15-14-11, 22-17-15-14-12, 22-17-15-14-13, which are group 17compounds in groups 17-15-14-1 through 17-15-14-13, (12) groups22-17-16-14-1, 22-17-16-14-2, 22-17-16-14-3, 22-17-16-14-4,22-17-16-14-5, 22-17-16-14-5A, 22-17-16-14-6, 22-17-16-14-7,22-17-16-14-8, 22-17-16-14-8A, 22-17-16-14-9, 22-17-16-14-10,22-17-16-14-10A, 22-17-16-14-11, 22-17-16-14-12, 22-17-16-14-13, whichare group 17 compounds in groups 17-16-14-1 through 17-15-14-13, (13)groups 22-17-16-15-1, 22-17-16-15-2, 22-17-16-15-3, 22-17-16-15-4,22-17-16-15-5, 22-17-16-15-5A, 22-17-16-15-6, 22-17-16-15-7,22-17-16-15-8, 22-17-16-15-8A, 22-17-16-15-9, 22-17-16-15-10,22-17-16-15-10A, 22-17-16-15-11, 22-17-16-15-12 and 22-17-16-15-13,which are group 17 compounds in groups 17-16-15-1 through 17-16-15-13,(14) groups 22-17-16-15-14-1, 22-17-16-15-14-2, 22-17-16-15-14-3,22-17-16-15-14-4, 22-17-16-15-14-5, 22-17-16-15-14-5A, 22-17-16-15-14-6,22-17-16-15-14-7, 22-17-16-15-14-8, 22-17-16-15-14-8A, 22-17-16-15-14-9,22-17-16-15-14-10, 22-17-16-15-14-10A, 22-17-16-15-14-11,22-17-16-15-14-12 and 22-17-16-15-14-13, which are group 17 compounds ingroups 17-16-15-14-1 through 17-16-15-14-13, (15) all of the compoundsand/or groups described in group 18, (16) all of the compounds and/orgroups described in group 19 and (17) all of the compounds and/or groupsdescribed in group 20.

Exemplary phosphate and phosphate esters include3β-hydroxyandrost-5-ene-17β-phosphate,3α-hydroxyandrost-5-ene-17β-phosphate,3β-hydroxy-16α-fluoroandrost-5-ene-17β-phosphate,3α-hydroxy-16α-fluoroandrost-5-ene-17β-phosphate,3β-hydroxy-5α-androstane-17β-phosphate,3α-hydroxy-5α-androstane-17β-phosphate,3β-hydroxy-5β-androstane-17β-phosphate,3α-hydroxy-5β-androstane-17β-phosphate, 3β-hydroxy-5α,14β-androstane-17β-phosphate, 3α-hydroxy-5α,14β-androstane-17β-phosphate, 3β-hydroxy-5β,14β-androstane-17β-phosphate, 3β-hydroxy-5β,14β-androstane-17α-phosphate, or a salt, 2-oxa analog, 1α-alkyl,4α-optionally substituted alkyl, 7-substituted analog, 16α-halo,16α-hydroxy, 19-nor or phosphate ester, e.g., phosphate methyl ester(—O—P(O)(O)—OCH₃), phosphate ethyl ester or phosphate optionallysubstituted alkyl ester of any of these compounds.

Group 23. This group contains compounds in groups 1-20 above where R⁴substituents 1-10 listed in Table A are replaced with the followinggroups: 1-phosphate thioether, 2-thionoester, 3-amino acid, 4-peptide,5-dipeptide, 6-optionally substituted heterocycle, 7-optionallysubstituted carboxyl, e.g., —COOH, —COOCH₃, —COOC₂H₅, —COOR^(PR) or—COO⁻Na⁺, 8-carbonate, e.g., optionally substituted alkylcarbonate suchas —O—C(O)—OCH₃ or —O—C(O)—OC₂H₅, 9-carbamate and 10 -phosphothioesteror a salt, e.g., Na⁺ or K⁺.

Amino acids for substituent 3 are as described herein and include, e.g.,—NH—CH₂—C(O)OH, —NH—CH₂—C(O)OR^(PR), —NH—CH₂—CH₂—C(O)OH,—NH—CH₂—CH₂—C(O)OR^(PR), —NH—CH(CH₃)—C(O)OH, —NH—CH(CH₃)—CH₂—C(O)OH,—NH—CH(CH₃)—CH₂—C(O)OR^(PR),—NH—CH₂—CH₂—CH₂—C(O)OH—NH—CH₂—CH₂—C—C(O)—CH₂—NH₂C—O—C(O)—CH₂—NHR^(PR),—O—C(O)—CH₂—CH₂—NH₂, —O—C(O)—CH₂—CH₂—NHR^(PR) or for ionizable groupssuch as free carboxyls or amines, a salt such as a Na⁺ or K⁺ salt forcarboxyls or a salt such as HCl or HBr salt for amines. Carbonates forsubstituent 8 are as described herein, e.g., —O—C(O)—OH, —O—C(O)—OCH₃,—O—C(O)—OCH₂OH, —O—C(O)—OCH₂F, —O—C(O)—OC₂H₅, —O—C(O)—OC₃H₇,—O—C(O)—OC₄H₉, —O—C(O)—O-optionally substituted alkyl,—O—C(O)—O-optionally substituted alkenyl, or —O—C(O)—O-optionallysubstituted monosaccharide. Carbamates for substituent 9 are asdescribed herein, e.g., —NH—C(O)—OCH₃, —NH—C(O)—OC₂H₅, —NH—C(O)—OC₃H₇,—NH—C(O)—OC₄H₉, —NH—C(O)—OC₆H₁₃, —NH—C(O)—OC₆H₅,—NH—C(O)—OC₆H₄—C(O)OR^(PR), —NH—C(O)—OCH₂OH, —NH—C(O)—OCH₂C(O)OH,—NH—C(O)—OCH₂-halogen, —NH—C(O)—OCHOH—CH₃, —NH—C(O)—O(CH₂)_(n)—OH,—NH—C(O)—OCH(CH₃)—(CH₂)_(n)—OH, —NH—C(O)—OCH(CH₃)—(CH₂)_(n)—C(O)OH,—NH—C(O)—O(CH₂)_(n)-halogen, —NH—C(O)—O(CH₂)_(n)—NH₂,—NH—C(O)—O(CH₂)_(n)—NHR^(PR), —NH—C(O)—O(CH₂)_(n)—C(O)OH,—NH—C(O)—OC₃H₆OH —NH—C(O)—OC₆H₄—F, —NH—C(O)—O-optionally substitutedalkyl, —NH—C(O)—O-optionally substituted alkenyl, —NH—C(O)—O-heterocycleor —NH—C(O)—O-optionally substituted monosaccharide, where n is 1, 2, 3,4, 5 or 6. Any of these alkyl or alkenyl groups may contain 1, 2, 3, 4,5, 6, 7, 8, 9,  or more atoms. Exemplary group 23 compounds include3β-hydroxyandrost-5-ene-17β-carbamate,3β-hydroxyandrost-1,5-diene-17β-carbamate,3α-hydroxyandrost-5-ene-17β-carbamate,3β-hydroxyandrost-5-ene-17α-carbamate,3α-hydroxyandrost-5-ene-17α-carbamate,3β-hydroxyandrost-4-ene-17β-carbamate,3α-hydroxyandrost-4-ene-17β-carbamate,3α-hydroxyandrost-1,4-diene-17β-carbamate,3β-hydroxyandrost-1,5,16-triene-17-carbamate, and analogs of any ofthese compounds having one, two or more moieties such as 16α-halo,16α-fluoro, 16β-fluoro, 16-fluoro, 16α-hydroxy, 7α-hydroxy or thiol,7β-hydroxy or thiol, 7-oxo, 7α-halo, 7β-halo, 7α-fluoro, 7β-fluoro,7α-alkoxy, 7β-alkoxy, 4α-halo, 4β-halo, 4α-alkyl, 4β-alkyl, 12α-halo,12β-halo, 12α-alkyl, 12β-alkyl, 11-dihalo, 11-dialkyl, 2-oxa, 11-oxa,19-nor or the like.

These compounds include compounds in group 23-1 through23-20-19-18-17-16-15-14-13, which collectively are group 23 compounds.These include groups 23-1, 23-2, 23-3, 23-4, 23-5, 23-5A, 23-6, 23-7,23-8, 23-8A, 23-9, 23-10, 23-10A, 23-11, 23-12, 23-13, which arecompounds in groups 1 through 13 where R⁴ substituents 1-10 in Table Aare replaced with the moieties given in this group. Group 23 compoundsalso include groups 23-14-1, 23-14-2, 23-14-3, 23-14-4, 23-14-5,23-14-5A, 23-14-6, 23-14-7, 23-14-8, 23-14-8A, 23-14-9, 23-14-10,23-14-10A, 23-14-11, 23-14-12 and 23-14-13, which are group 14 compoundsin groups 14-1 through 14-13 where R⁴ substituents 1-10 in Table A arereplaced with the moieties given in this group.

Other group 23 compounds include (1) groups 23-15-1, 23-15-2, 23-15-3,23-15-4, 23-15-5, 23-15-5A, 23-15-6, 23-15-7, 23-15-8, 23-15-8A,23-15-9, 23-15-10, 23-15-10A, 23-15-11, 23-15-12 and 23-15-13, which aregroup 15 compounds in groups 15-1 through 15-13, (2) groups 23-16-1,23-16-2, 23-16-3, 23-16-4, 23-16-5, 23-16-5A, 23-16-6, 23-16-7, 23-16-8,23-16-8A, 23-16-9, 23-16-10, 23-16-10A, 23-16-11, 23-16-12 and 23-16-13,which are group 16 compounds in groups 16-1 through 16-13, (3) groups23-17-1, 23-17-2, 23-17-3, 23-17-4, 23-17-5, 23-17-5A, 23-17-6, 23-17-7,23-17-8, 23-17-8A, 23-17-9, 23-17-10, 23-17-10A, 23-17-11, 23-17-12 and23-17-13, which are group 17 compounds in groups 17-1 through 17-13, (4)groups 23-15-14-1, 23-15-14-2, 23-15-14-3, 23-15-14-4, 23-15-14-5,23-15-14-5A, 23-15-14-6, 23-15-14-7, 23-15-14-8, 23-15-14-8A,23-15-14-9, 23-15-14-10, 23-15-14-10A, 23-15-14-11, 23-15-14-12 and23-15-14-13, which are group 15 compounds in groups 15-14-1 through15-14-13, (5) groups 23-16-14-1, 23-16-14-2, 23-16-14-3, 23-16-14-4,23-16-14-5, 23-16-14-5A, 23-16-14-6, 23-16-14-7, 23-16-14-8,23-16-14-8A, 23-16-14-9, 23-16-14-10, 23-16-14-10A, 23-16-14-11,23-16-14-12 and 23-16-14-13, which are group 16 compounds in groups16-14-1 through 16-14-13, (6) groups 23-17-14-1, 23-17-14-2, 23-17-14-3,23-17-14-4, 23-17-14-5, 23-17-14-5A, 23-17-14-6, 23-17-14-7, 23-17-14-8,23-17-14-8A, 23-17-14-9, 23-17-14-10, 23-17-14-10A, 23-17-14-11,23-17-14-12, 23-17-14-13, which are group 17 compounds in groups 17-14-1through 17-14-13, (7) groups 23-16-15-1, 23-16-15-2, 23-16-15-3,23-16-15-4, 23-16-15-5, 23-16-15-5A, 23-16-15-6, 23-16-15-7, 23-16-15-8,23-16-15-8A, 23-16-15-9, 23-16-15-10, 23-16-15-10A, 23-16-15-11,23-16-15-12, 23-16-15-13, which are group 16 compounds in groups 16-15-1through 16-15-13, (8) groups 23-17-15-1, 23-17-15-2, 23-17-15-3,23-17-15-4, 23-17-15-5, 23-17-15-5A, 23-17-15-6, 23-17-15-7, 23-17-15-8,23-17-15-8A, 23-17-15-9, 23-17-15-10, 23-17-15-10A, 23-17-15-11,23-17-15-12, 23-17-15-13, which are group 17 compounds in groups 17-15-1through 17-15-13, (9) groups 23-17-16-1, 23-17-16-2, 23-17-16-3,23-17-16-4, 23-17-16-5, 23-17-16-5A, 23-17-16-6, 23-17-16-7, 23-17-16-8,23-17-16-8A, 23-17-16-9, 23-17-16-10, 23-17-16-10A, 23-17-16-11,23-17-16-12, 23-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13, (10) groups 23-16-15-14-1, 23-16-15-14-2,23-16-15-14-3, 23-16-15-14-4, 23-16-15-14-5, 23-16-15-14-5A,23-16-15-14-6, 23-16-15-14-7, 23-16-15-14-8, 23-16-15-14-8A,23-16-15-14-9, 23-16-15-14-10, 23-16-15-14-10A, 23-16-15-14-11,23-16-15-14-12, 23-16-15-14-13, which are group 16 compounds in groups16-15-14-1 through 16-15-14-13, (11) groups 23-17-15-14-1,23-17-15-14-2, 23-17-15-14-3, 23-17-15-14-4, 23-17-15-14-5,23-17-15-14-5A, 23-17-15-14-6, 23-17-15-14-7, 23-17-15-14-8,23-17-15-14-8A, 23-17-15-14-9, 23-17-15-14-10, 23-17-15-14-10A,23-17-15-14-11, 23-17-15-14-12, 23-17-15-14-13, which are group 17compounds in groups 17-15-14-1 through 17-15-14-13, (12) groups23-17-16-14-1, 23-17-16-14-2, 23-17-16-14-3, 23-17-16-14-4,23-17-16-14-5, 23-17-16-14-5A, 23-17-16-14-6, 23-17-16-14-7,23-17-16-14-8, 23-17-16-14-8A, 23-17-16-14-9, 23-17-16-14-10,23-17-16-14-10A, 23-17-16-14-11, 23-17-16-14-12, 23-17-16-14-13, whichare group 17 compounds in groups 17-16-14-1 through 17-15-14-13, (13)groups 23-17-16-15-1, 23-17-16-15-2, 23-17-16-15-3, 23-17-16-15-4,23-17-16-15-5, 23-17-16-15-5A, 23-17-16-15-6, 23-17-16-15-7,23-17-16-15-8, 23-17-16-15-8A, 23-17-16-15-9, 23-17-16-15-10,23-17-16-15-10A, 23-17-16-15-11, 23-17-16-15-12 and 23-17-16-15-13,which are group 17 compounds in groups 17-16-15-1 through 17-16-15-13,(14) groups 23-17-16-15-14-1, 23-17-16-15-14-2, 23-17-16-15-14-3,23-17-16-15-14-4, 23-17-16-15-14-5, 23-17-16-15-14-5A, 23-17-16-15-14-6,23-17-16-15-14-7, 23-17-16-15-14-8, 23-17-16-15-14-8A, 23-17-16-15-14-9,23-17-16-15-14-10, 23-17-16-15-14-10A, 23-17-16-15-14-11,23-17-16-15-14-12 and 23-17-16-15-14-13, which are group 17 compounds ingroups 17-16-15-14-1 through 17-16-15-14-13, (15) all of the compoundsand/or groups described in group 18, (16) all of the compounds and/orgroups described in group 19 and (17) all of the compounds and/or groupsdescribed in group 20.

Group 24. This group contains compounds in groups 1-20 above where R⁴substituents 1-10 listed in Table A are replaced with the followinggroups: 1 -thiophosphate or a salt, 2-phosphothioether, 3-thiophosphatethioether, 4 -phosphonoester, 5-phosphonate or a salt, 6-phosphonateester, 7-phosphonate ether, 8-phosphonate thioether, 9 —O—S(O)(O)—OH ora -sulfate salt, e.g., —O—S(O)(O)—O⁺Na⁻, 10 —F, —Cl, —Br or —I.

Group 25. This group contains compounds in groups 1-20 above where R⁴substituents 1-10 listed in Table A are replaced with the followinggroups: 1-sulfate ester, 2-sulfate ether, 3-sulfate thioether, 4—O—S(O)—OH, 5-sulfite salt, e.g., —O—S(O)—O⁺Na⁻, 6-sulfite ester, 7-sulfite ether, 8-sulfoxide, 9 —O—S(O)(O)—OR^(PR) and 10—O—S(O)(O)—OCH₃.

Exemplary sulfate esters include optionally substituted alkyl esters,e.g., methyl, ethyl, propyl or butyl ester, of3β-hydroxyandrost-5-ene-17β-sulfate,3α-hydroxyandrost-5-ene-17β-sulfate,3β-hydroxy-16α-fluoroandrost-5-ene-17β-sulfate,3α-hydroxy-16α-fluoroandrost-5-ene-17β-sulfate,3β-hydroxy-5α-androstane-17β-sulfate,3α-hydroxy-5α-androstane-17β-sulfate,3β-hydroxy-5β-androstane-17β-sulfate,3α-hydroxy-5β-androstane-17β-sulfate, 3β-hydroxy-5α,14β-androstane-17β-sulfate, 3α-hydroxy-5α, 14β-androstane-17β-sulfate,3β-hydroxy-5β, 14β-androstane-17β-sulfate, 3β-hydroxy-5β,14β-androstane-17α-sulfate, or a salt, 2-oxa analog, 1α-alkyl, 10-alkyl,4α-optionally substituted alkyl, 4β-optionally substituted alkyl,7-substituted analog, 16α-halo, 16α-hydroxy, or 19-nor analog of any ofthese compounds.

Group 26. This group contains compounds in groups 1-20 above where R⁴substituents 1-10 listed in Table A are replaced with the followinggroups: 1-sulfonamide, 2-sulfonamide derivative, e.g., —S(O)(O)—NHR^(PR)or —S(O)(O)—NH-optionally substituted alkyl, 3-sulfamate, 4-sulfamatederivative, e.g., —O—S(O)(O)—NHR^(PR), —O—S(O)(O)—N(RD)₂ or—O—S(O)(O)—NH-optionally substituted alkyl, 5-sulfonate, 6-sulfamide,7-sulfinamide, 8-sulfurous diamide, 9-optionally protectedmonosaccharide, e.g., D-, L- or DL-glucose, galactose, fructose,rhamnose or glucuronic acid, 10-optionally protected oligosaccharide,e.g., D-, L- or DL-galactose-galactose, -galactose-mannose or-glucuronic acid-glucose. In this group, the optionally protectedmonosaccharide and optionally protected oligomonosaccharide moieties aretypically linked to the 17-position through an oxygen, sulfur ornitrogen atom.

Exemplary group 26 compounds include glycosides such as 17β-glycosidesand 17α-glycosides,3β,16α-dihydroxyandrost-5-ene-17β-O-1′-β′-glucopyranose,3α,16α-dihydroxyandrost-5-ene-17β-O-1′-β′-glucopyranose,3α-hydroxy-16α-fluoroandrost-5-ene-17β-O-1′-β′-glucopyranose,3β,16α-dihydroxyandrost-5-ene-17α-O-1′-β′-glucopyranose,3α,16α-dihydroxyandrost-5-ene-17α-O-1′-β′-glucopyranose,3α-hydroxy-16β-fluoroandrost-5-ene-17α-O-1′-β′-glucopyranose and analogsof any of these compounds having one, two or more moieties describedherein for variable groups, e.g., 16α-halo, 16β-halo, 7α-hydroxy orthiol, 7β-hydroxy or thiol, 7-oxo, 7α-halo, 7β-halo, 7α-fluoro,7β-fluoro, 7α-alkoxy, 7β-alkoxy, 4α-halo, 4β-halo, 4α-alkyl, 4β-alkyl,12α-halo, 12β-halo, 12α-alkyl, 12β-alkyl, 11-dihalo, 11-alkyl,11α-alkyl, 11-dialkyl, 2-oxa, 11-oxa, 15-oxa, 19-nor (i.e., R⁶ is —H),18-homo (i.e., R⁵ is —C₂H₅) or the like where any alkyl or alkoxymoieties are optionally substituted. Other exemplary moieties at R⁴include β-D-glucopyranosyl, β-D-glucopyranuronosyl,β-D-2-acetamido-2-deoxy-glucopyranosyl, β-D-galactopyranosyl,β-D-fucopyranosyl, β-L-fucopyranosyl, α-D-fructofuranosyl,β-D-fructofuranosyl, β-D-xylopyranosyl, β-L-xylopyranosyl,α-D-arabanopyranosyl, α-L-arabanopyranosyl, α-L-rhamnopyranosyl,α-D-rhamnopyranosyl, α-D-cellobiosyl, β-D-cellobiosyl, β-D-lactosyl,β-D-maltosyl, β-D-gentiobiosyl,3-O-β-D-galactopyranosyl-α-D-arabanopyranosyl or β-D-maltotriosyl, anyof which are optionally protected and where R⁴ is in the α- orβ-configuration.

These compounds include compounds in group 26-1 through26-20-19-18-17-16-15-14-13, which collectively are group 26 compounds.These include groups 26-1, 26-2, 26-3, 26-4, 26-5, 26-5A, 26-6, 26-7,26-8, 26-8A, 26-9, 26-10, 26-10A, 26-11, 26-12, 26-13, which arecompounds in groups 1 through 13 where R⁴ substituents 1-10 in Table Aare replaced with the moieties given in this group. Group 26 compoundsalso include groups 26-14-1, 26-14-2, 26-14-3, 26-14-4, 26-14-5,26-14-5A, 26-14-6, 26-14-7, 26-14-8, 26-14-8A, 26-14-9, 26-14-10,26-14-10A, 26-14-11, 26-14-12 and 26-14-13, which are group 14 compoundsin groups 14-1 through 14-13 where R⁴ substituents 1-10 in Table A arereplaced with the moieties given in this group.

Other group 26 compounds include (1) groups 26-15-1, 26-15-2, 26-15-3,26-15-4, 26-15-5, 26-15-5A, 26-15-6, 26-15-7, 26-15-8, 26-15-8A,26-15-9, 26-15-10, 26-15-10A, 26-15-11, 26-15-12 and 26-15-13, which aregroup 15 compounds in groups 15-1 through 15-13, (2) groups 26-16-1,26-16-2, 26-16-3, 26-16-4, 26-16-5, 26-16-5A, 26-16-6, 26-16-7, 26-16-8,26-16-8A, 26-16-9, 26-16-10, 26-16-10A, 26-16-11, 26-16-12 and 26-16-13,which are group 16 compounds in groups 16-1 through 16-13, (3) groups26-17-1, 26-17-2, 26-17-3, 26-17-4, 26-17-5, 26-17-5A, 26-17-6, 26-17-7,26-17-8, 26-17-8A, 26-17-9, 26-17-10, 26-17-10A, 26-17-11, 26-17-12 and26-17-13, which are group 17 compounds in groups 17-1 through 17-13, (4)groups 26-15-14-1, 26-15-14-2, 26-15-14-3, 26-15-14-4, 26-15-14-5,26-15-14-5A, 26-15-14-6, 26-15-14-7, 26-15-14-8, 26-15-14-8A,26-15-14-9, 26-15-14-10, 26-15-14-10A, 26-15-14-11, 26-15-14-12 and26-15-14-13, which are group 15 compounds in groups 15-14-1 through15-14-13, (5) groups 26-16-14-1, 26-16-14-2, 26-16-14-3, 26-16-14-4,26-16-14-5, 26-16-14-5A, 26-16-14-6, 26-16-14-7, 26-16-14-8,26-16-14-8A, 26-16-14-9, 26-16-14-10, 26-16-14-10A, 26-16-14-11,26-16-14-12 and 26-16-14-13, which are group 16 compounds in groups16-14-1 through 16-14-13, (6) groups 26-17-14-1, 26-17-14-2, 26-17-14-3,26-17-14-4, 26-17-14-5, 26-17-14-5A, 26-17-14-6, 26-17-14-7, 26-17-14-8,26-17-14-8A, 26-17-14-9, 26-17-14-10, 26-17-14-10A, 26-17-14-11,26-17-14-12, 26-17-14-13, which are group 17 compounds in groups 17-14-1through 17-14-13, (7) groups 26-16-15-1, 26-16-15-2, 26-16-15-3,26-16-15-4, 26-16-15-5, 26-16-15-5A, 26-16-15-6, 26-16-15-7, 26-16-15-8,26-16-15-8A, 26-16-15-9, 26-16-15-10, 26-16-15-10A, 26-16-15-11,26-16-15-12, 26-16-15-13, which are group 16 compounds in groups 16-15-1through 16-15-13, (8) groups 26-17-15-1, 26-17-15-2, 26-17-15-3,26-17-15-4, 26-17-15-5, 26-17-15-5A, 26-17-15-6, 26-17-15-7, 26-17-15-8,26-17-15-8A, 26-17-15-9, 26-17-15-10, 26-17-15-10A, 26-17-15-11,26-17-15-12, 26-17-15-13, which are group 17 compounds in groups 17-15-1through 17-15-13, (9) groups 26-17-16-1, 26-17-16-2, 26-17-16-3,26-17-16-4, 26-17-16-5, 26-17-16-5A, 26-17-16-6, 26-17-16-7, 26-17-16-8,26-17-16-8A, 26-17-16-9, 26-17-16-10, 26-17-16-10A, 26-17-16-11,26-17-16-12, 26-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13, (10) groups 26-16-15-14-1, 26-16-15-14-2,26-16-15-14-3, 26-16-15-14-4, 26-16-15-14-5, 26-16-15-14-5A,26-16-15-14-6, 26-16-15-14-7, 26-16-15-14-8, 26-16-15-14-8A,26-16-15-14-9, 26-16-15-14-10, 26-16-15-14-10A, 26-16-15-14-11,26-16-15-14-12, 26-16-15-14-13, which are group 16 compounds in groups16-15-14-1 through 16-15-14-13, (11) groups 26-17-15-14-1,26-17-15-14-2, 26-17-15-14-3, 26-17-15-14-4, 26-17-15-14-5,26-17-15-14-5A, 26-17-15-14-6, 26-17-15-14-7, 26-17-15-14-8,26-17-15-14-8A, 26-17-15-14-9, 26-17-15-14-10, 26-17-15-14-10A,26-17-15-14-11, 26-17-15-14-12, 26-17-15-14-13, which are group 17compounds in groups 17-15-14-1 through 17-15-14-13, (12) groups26-17-16-14-1, 26-17-16-14-2, 26-17-16-14-3, 26-17-16-14-4,26-17-16-14-5, 26-17-16-14-5A, 26-17-16-14-6, 26-17-16-14-7,26-17-16-14-8, 26-17-16-14-8A, 26-17-16-14-9, 26-17-16-14-10,26-17-16-14-10A, 26-17-16-14-11, 26-17-16-14-12, 26-17-16-14-13, whichare group 17 compounds in groups 17-16-14-1 through 17-15-14-13, (13)groups 26-17-16-15-1, 26-17-16-15-2, 26-17-16-15-3, 26-17-16-15-4,26-17-16-15-5, 26-17-16-15-5A, 26-17-16-15-6, 26-17-16-15-7,26-17-16-15-8, 26-17-16-15-8A, 26-17-16-15-9, 26-17-16-15-10,26-17-16-15-10A, 26-17-16-15-11, 26-17-16-15-12 and 26-17-16-15-13,which are group 17 compounds in groups 17-16-15-1 through 17-16-15-13,(14) groups 26-17-16-15-14-1, 26-17-16-15-14-2, 26-17-16-15-14-3,26-17-16-15-14-4, 26-17-16-15-14-5, 26-17-16-15-14-5A, 26-17-16-15-14-6,26-17-16-15-14-7, 26-17-16-15-14-8, 26-17-16-15-14-8A, 26-17-16-15-14-9,26-17-16-15-14-10, 26-17-16-15-14-10A, 26-17-16-15-14-11,26-17-16-15-14-12 and 26-17-16-15-14-13, which are group 17 compounds ingroups 17-16-15-14-1 through 17-16-15-14-13, (15) all of the compoundsand/or groups described in group 18, (16) all of the compounds and/orgroups described in group 19 and (17) all of the compounds and/or groupsdescribed in group 20.

Group 26A. This group contains compounds in groups 1-20 above where R⁴substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —N-pyrrolidine, 2 —N1-pyrazolone, 3 —N2-pyrazolone, 4—N-imidazolidin-2-one, 5 —N1-imidazole, 6 —N1-4,5-dihydroimidazole, 7—N-morpholine, 8 —N1-pyridine, 9 —N-piperidine, 10 —N-piperazine.

These compounds include compounds in group 26A-1 through23-20-19-18-17-16-15-14-13, which collectively are group 26 compounds.These include groups 26A-1, 26A-2, 26A-3, 26A-4, 26A-5, 26A-5A, 26A-6,26A-7, 26A-8, 26A-8A, 26-9, 26A-10, 26A-10A, 26A-11, 26A-12, 26A-13,which are compounds in groups 1 through 13 where R⁴ substituents 1-10 inTable A are replaced with the moieties given in this group. Group 26Acompounds also include groups 26A-14-1, 26A-14-2, 26A-14-3, 26A-14-4,26A-14-5, 26A-14-5A, 26A-14-6, 26A-14-7, 26A-14-8, 26A-14-8A, 26A-14-9,26A-14-10, 26A-14-10A, 26A-14-11, 26A-14-12 and 26A-14-13, which aregroup 14 compounds in groups 14-1 through 14-13 where R⁴ substituents1-10 in Table A are replaced with the moieties given in this group.

Other group 26A compounds include (1) groups 26A-15-1, 26A-15-2,26A-15-3, 26A-15-4, 26A-15-5, 26A-15-5A, 26A-15-6, 26A-15-7, 26A-15-8,26A-15-8A, 26A-15-9, 26A-15-10, 26A-15-10A, 26A-15-11, 26A-15-12 and26A-15-13, which are group 15 compounds in groups 15-1 through 15-13,(2) groups 26A-16-1, 26A-16-2, 26A-16-3, 26A-16-4, 26A-16-5, 26A-16-5A,26A-16-6, 26A-16-7, 26A-16-8, 26A-16-8A, 26A-16-9, 26A-16-10,26A-16-10A, 26A-16-11, 26A-16-12 and 26A-16-13, which are group 16compounds in groups 16-1 through 16-13, (3) groups 26A-17-1, 26A-17-2,26A-17-3, 26A-17-4, 26A-17-5, 26A-17-5A, 26A-17-6, 26A-17-7, 26A-17-8,26A-17-8A, 26A-17-9, 26A- 17-10, 26A-17-10A, 26A-17-11, 26A-17-12 and26A-17-13, which are group 17 compounds in groups 17-1 through 17-13,(4) groups 26A-15-14-1, 26A-15-14-2, 26A-15-14-3, 26A-15-14-4,26A-15-14-5, 26A-15-14-5A, 26A-15-14-6, 26A-15-14-7, 26A-15-14-8,26A-15-14-8A, 26A-15-14-9, 26A-15-14-10, 26A-15-14-10A, 26A-15-14-11,26A-15-14-12 and 26A-15-14-13, which are group 15 compounds in groups15-14-1 through 15-14-13, (5) groups 26A-16-14-1, 26A-16-14-2,26A-16-14-3, 26A-16-14-4, 26A-16-14-5, 26A-16-14-5A, 26A-16-14-6,26A-16-14-7, 26A-16-14-8, 26A-16-14-8A, 26A-16-14-9, 26A-16-14-10,26A-16-14-10A, 26A-16-14-11, 26A-16-14-12 and 26A-16-14-13, which aregroup 16 compounds in groups 16-14-1 through 16-14-13, (6) groups26A-17-14-1, 26A-17-14-2, 26A-17-14-3, 26A-17-14-4, 26A-17-14-5,26A-17-14-5A, 26A-17-14-6, 26A-17-14-7, 26A-17-14-8, 26A-17-14-8A,26A-17-14-9, 26A-17-14-10, 26A-17-14-10A, 26A-17-14-11, 26A-17-14-12,26A-17-14-13, which are group 17 compounds in groups 17-14-1 through17-14-13, (7) groups 26A-16-15-1, 26A-16-15-2, 26A-16-15-3, 26A-16-15-4,26A-16-15-5, 26A-16-15-5A, 26A-16-15-6, 26A-16-15-7, 26A-16-15-8,26A-16-15-8A, 26A-16-15-9, 26A-16-15-10, 26A-16-15-10A, 26A-16-15-11,26A-16-15-12, 26A-16-15-13, which are group 16 compounds in groups16-15-1 through 16-15-13, (8) groups 26A-17-15-1, 26A-17-15-2,26A-17-15-3, 26A-17-15-4, 26A-17-15-5, 26A-17-15-5A, 26A-17-15-6,26A-17-15-7, 26A-17-15-8, 26A-17-15-8A, 26A-17-15-9, 26A-17-15-10,26A-17-15-10A, 26A-17-15-11, 26A-17-15-12, 26A-17-15-13, which are group17 compounds in groups 17-15-1 through 17-15-13, (9) groups 26A-17-16-1,26A-17-16-2, 26A-17-16-3, 26A-17-16-4, 26A-17-16-5, 26A-17-16-5A,26A-17-16-6, 26A-17-16-7, 26A-17-16-8, 26A-17-16-8A, 26A-17-16-9,26A-17-16-10, 26A-17-16-10A, 26A-17-16-11, 26A-17-16-12, 26A-17-16-13,which are group 17 compounds in groups 17-16-1 through 17-16-13, (10)groups 26A-16-15-14-1, 26A-16-15-14-2, 26A-16-15-14-3, 26A-16-15-14-4,26A-16-15-14-5, 26A-16-15-14-5A, 26A-16-15-14-6, 26A-16-15-14-7,26A-16-15-14-8, 26A-16-15-14-8A, 26A-16-15-14-9, 26A-16-15-14-10,26A-16-15-14-10A, 26A-16-15-14-11, 26A-16-15-14-12, 26A-16-15-14-13,which are group 16 compounds in groups 16-15-14-1 through 16-15-14-13,(11) groups 26A-17-15-14-1, 26A-17-15-14-2, 26A-17-15-14-3,26A-17-15-14-4, 26A-17-15-14-5, 26A-17-15-14-5A, 26A-17-15-14-6,26A-17-15-14-7, 26A-17-15-14-8, 26A-17-15-14-8A, 26A-17-15-14-9,26A-17-15-14-10, 26A-17-15-14-10A, 26A-17-15-14-11, 26A-17-15-14-12,26A-17-15-14-13, which are group 17 compounds in groups 17-15-14-1through 17-15-14-13, (12) groups 26A-17-16-14-1, 26A-17-16-14-2,26A-17-16-14-3, 26A-17-16-14-4, 26A-17-16-14-5, 26A-17-16-14-5A,26A-17-16-14-6, 26A-17-16-14-7, 26A-17-16-14-8, 26A-17-16-14-8A,26A-17-16-14-9, 26A-17-16-14-10, 26A-17-16-14-10A, 26A-17-16-14-11,26A-17-16-14-12, 26A-17-16-14-13, which are group 17 compounds in groups17-16-14-1 through 17-15-14-13, (13) groups 26A-17-16-15-1,26A-17-16-15-2, 26A-17-16-15-3, 26A-17-16-15-4, 26A-17-16-15-5,26A-17-16-15-5A, 26A-17-16-15-6, 26A-17-16-15-7, 26A-17-16-15-8,26A-17-16-15-8A, 26A-17-16-15-9, 26A-17-16-15-10, 26A-17-16-15-10A,26A-17-16-15-11, 26A-17-16-15-12 and 26A-17-16-15-13, which are group 17compounds in groups 17-16-15-1 through 17-16-15-13, (14) groups26A-17-16-15-14-1, 26A-17-16-15-14-2, 26A-17-16-15-14-3,26A-17-16-15-14-4, 26A-17-16-15-14-5, 26A-17-16-15-14-5A,26A-17-16-15-14-6, 26A-17-16-15-14-7, 26A-17-16-15-14-8,26A-17-16-15-14-8A, 26A-17-16-15-14-9, 26A-17-16-15-14-10,26A-17-16-15-14-10A, 26A-17-16-15-14-11, 26A-17-16-15-14-12 and26A-17-16-15-14-13, which are group 17 compounds in groups 17-16-15-14-1through 17-16-15-14-13, (15) all of the compounds and/or groupsdescribed in group 18, (16) all of the compounds and/or groups describedin group 19 and (17) all of the compounds and/or groups described ingroup 20.

Group 26B. This group contains compounds in groups 1-20 above where R⁴substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —N-piperazine substituted at N4 with optionally substitutedalkyl, 2 —N-indole, 3 —N-indoline, 4 —N-quinolidine, 5—NH—C(O)—CH₂—CH₂—C(O)—OH, 6 —NH—C(O)—CH₂—C(O)—OH, 7—NH—C(O)—CH₂—CH₂—C(O)—OR^(PR), 8 —NH—C(O)—CH₂—C(O)—OR^(PR), 9—NH—C(O)—(CH₂)₃—C(O)—OH, 10 —NH—C(O)—(CH₂)₃—C(O)—OR^(PR). Ionizablemoieties such as free carboxyl groups include salts, e.g., Na⁺ or K⁺.R^(PR) is a protecting group.

Group 26C. This group contains compounds in groups 1-20 above where R⁴substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —NH—CH(CH₃)—C(O)OH, 2 —NH—CH(CH₃)—C(O)OR^(PR), 3—NH—CH(CH₂OH)—C(O)OH, 4 —NH—CH(CH₂OH)—C(O)OR^(PR), 5—NH—CH₂—CH₂—C(O)—OH, 6 —NH—CH₂—C(O)—OH, 7 —NH—CH₂—CH₂—C(O)—OR^(PR), 8—NH—CH₂—C(O)—OR^(PR), 9 —NH—(CH₂)₃—C(O)—OH, 10 —NH—(CH₂)₃—C(O)—OR^(PR).Ionizable moieties such as free carboxyl groups include salts, e.g., Na⁺or K⁺. R^(PR) is a protecting group.

Group 26D. This group contains compounds in groups 1-20 above where R⁴substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —NH—CH(CH₃)—C(O)OH, 2 —NH—NH—C(O)CH₃, 3 —NH—NH—C(O)OCH₃, 4—NH—NH—C(O)C₂H₅, 5 —NH—NH—C(O)OC₂H₅, 6 —NH—NH—C(O)C₃H₇, 7—NH—NH—C(O)-optionally substituted alkyl, 8 —NH—C(NH-optionallysubstituted alkyl)=N-optionally substituted alkyl, 9—NH—C(NH—CH₃)═N—CH₃, 10 —NH—C(NH—C₂H₅)═N—C₂H₅.

Group 26E. This group contains compounds in groups 1-20 above where R⁴substituents 1-10 listed in Table A are replaced with the followinggroups: 1 spiro β-NH—(CH₂)₂—O-α, 2 spiro α-NH—(CH₂)₂—O-β, 3 spiroβ-NH—(CH₂)₂—NH-α, 4 spiro α-NH—(CH₂)₂—NH-β, 5 spiro β-NH—CH═N—CH₂-α, 6spiro α-NH—CH═N—CH₂-β, 7 spiro β-NH—CHR¹⁰—CHR¹⁰—O-α, 8 spiroα-NH—CHR¹⁰—CHR¹⁰—O-β, 9 spiro β-NH—CHR¹⁰—CHR¹⁰—NH-α, 10 spiroα-NH—CHR¹⁰—CHR¹⁰—NH-β. Each R¹⁰ is independently chosen and has themeaning given above, e.g., —H, —OH, ═O, —SH, ═S, halogen or optionallysubstituted alkyl.

Group 27. This group contains compounds in groups 1-20 above where R⁴substituents 1-10 listed in Table A are replaced with the followinggroups: 1-glycol, e.g., propylene glycol or ethylene glycol,2-polyethylene glycol, e.g., PEG 100 or PEG 200, 3-an acetal ring, 4-aspiro ring, 5-a thioacetal ring, 6 spiro —O—CH₂—O—, 7 spiro—O—(CH₂)₂—O—, 8 spiro —NH—(CH₂)₂—O—, 9 —NH—C(O)—(CH₂)₂—C(O)O—CH₃, 10—NH—C(O)—(CH₂)₂—C(O)—OH.

Group 28. This group contains compounds in groups 1-27 above where R¹substituents 1-10 listed in Table A are replaced with the followinggroups: 1-optionally substituted amine, 2-optionally substituted amide,3-optionally substituted oxime, 4-optionally substituted alkyl,5-optionally substituted alkenyl, 6-optionally substituted alkynyl,7-optionally substituted aryl, 8-optionally substituted heterocycle,9-ether and 10-ester. Any of these groups can be a moiety defined hereinfor that group. Thus, for Table A substituent 1, optionally substitutedamine, the R¹ group includes moieties such as —NH₂, —NH₃ ⁺Cl⁻, —NH₃⁺Br⁻, —NH₃ ⁺I⁻, optionally substituted alkylamine, di-optionallysubstituted alkylamine, —NH—CH₃, —N(CH₃)₂, —N(C₂H₅)₂, —N(n-propyl)₂,—N(i-propyl)₂, —N(n-butyl)₂, —N(t-butyl)₂, —NH—C₁₋₄ alkyl, —NH—C₁₋₄hydroxyalkyl, —NH—C₁₋₄ fluoroalkyl, —NH—CH₂—CH₂—O—CH₃, —NH-optionallysubstituted alkyl, —N(optionally substituted alkyl)₂, —NH—C₆H₅,—N(C₆H₅)₂, —NH-optionally substituted monosaccharide and —NH-optionallysubstituted oligosaccharide, and optionally substituted amide includes—NHC(O)-optionally substituted alkyl, —N(CH₃)—C(O)-optionallysubstituted alkyl, —N(C₂H₅)—C(O)-optionally substituted alkyl,—N(C₃H₇)—C(O)-optionally substituted alkyl, —N(C₄H₉)—C(O)-optionallysubstituted alkyl, —N(C₆H₅)—C(O)-optionally substituted alkyl,—NH—C(O)-optionally substituted monosaccharide and —NH—C(O)-optionallysubstituted oligosaccharide, where alkyl or phenyl groups are the sameor different and are optionally substituted as described herein.

These compounds include compounds in group 28-1 through28-27-20-19-18-17-16-15-14-13, which collectively are group 28compounds. These include groups 28-1, 28-2, 28-3, 28-4, 28-5, 28-5A,28-6, 28-7, 28-8, 28-8A, 28-9, 28-10, 28-10A, 28-11, 28-12, 28-13, whichare compounds in groups 1 through 13 where R¹ substituents 1-10 in TableA are replaced with the moieties given in this group. Group 28 compoundsalso include groups 28-14-1, 28-14-2, 28-14-3, 28-14-4, 28-14-5,28-14-5A, 28-14-6, 28-14-7, 28-14-8, 28-14-8A, 28-14-9, 28-14-10,28-14-10A, 28-14-11, 28-14-12 and 28-14-13, which are group 14 compoundsin groups 14-1 through 14-13 where R¹ substituents 1-10 in Table A arereplaced with the moieties given in this group.

Other group 28 compounds include (1) groups 28-15-1, 28-15-2, 28-15-3,28-15-4, 28-15-5, 28-15-5A, 28-15-6, 28-15-7, 28-15-8, 28-15-8A,28-15-9, 28-15-10, 28-15-10A, 28-15-11, 28-15-12 and 28-15-13, which aregroup 15 compounds in groups 15-1 through 15-13, (2) groups 28-16-1,28-16-2, 28-16-3, 28-16-4, 28-16-5, 28-16-5A, 28-16-6, 28-16-7, 28-16-8,28-16-8A, 28-16-9, 28-16-10, 28-16-10A, 28-16-11, 28-16-12 and 28-16-13,which are group 16 compounds in groups 16-1 through 16-13, (3) groups28-17-1, 28-17-2, 28-17-3, 28-17-4, 28-17-5, 28-17-5A, 28-17-6, 28-17-7,28-17-8, 28-17-8A, 28-17-9, 28-17-10, 28-17-10A, 28-17-11, 28-17-12 and28-17-13, which are group 17 compounds in groups 17-1 through 17-13, (4)groups 28-15-14-1, 28-15-14-2, 28-15-14-3, 28-15-14-4, 28-15-14-5,28-15-14-5A, 28-15-14-6, 28-15-14-7, 28-15-14-8, 28-15-14-8A,28-15-14-9, 28-15-14-10, 28-15-14-10A, 28-15-14-11, 28-15-14-12 and28-15-14-13, which are group 15 compounds in groups 15-14-1 through15-14-13, (5) groups 28-16-14-1, 28-16-14-2, 28-16-14-3, 28-16-14-4,28-16-14-5, 28-16-14-5A, 28-16-14-6, 28-16-14-7, 28-16-14-8,28-16-14-8A, 28-16-14-9, 28-16-14-10, 28-16-14-10A, 28-16-14-11,28-16-14-12 and 28-16-14-13, which are group 16 compounds in groups16-14-1 through 16-14-13, (6) groups 28-17-14-1, 28-17-14-2, 28-17-14-3,28-17-14-4, 28-17-14-5, 28-17-14-5A, 28-17-14-6, 28-17-14-7, 28-17-14-8,28-17-14-8A, 28-17-14-9, 28-17-14-10, 28-17-14-10A, 28-17-14-11,28-17-14-12, 28-17-14-13, which are group 17 compounds in groups 17-14-1through 17-14-13, (7) groups 28-16-15-1, 28-16-15-2, 28-16-15-3,28-16-15-4, 28-16-15-5, 28-16-15-5A, 28-16-15-6, 28-16-15-7, 28-16-15-8,28-16-15-8A, 28-16-15-9, 28-16-15-10, 28-16-15-10A, 28-16-15-11,28-16-15-12, 28-16-15-13, which are group 16 compounds in groups 16-15-1through 16-15-13, (8) groups 28-17-15-1, 28-17-15-2, 28-17-15-3,28-17-15-4, 28-17-15-5, 28-17-15-5A, 28-17-15-6, 28-17-15-7, 28-17-15-8,28-17-15-8A, 28-17-15-9, 28-17-15-10, 28-17-15-10A, 28-17-15-11,28-17-15-12, 28-17-15-13, which are group 17 compounds in groups 17-15-1through 17-15-13, (9) groups 28-17-16-1, 28-17-16-2, 28-17-16-3,28-17-16-4, 28-17-16-5, 28-17-16-5A, 28-17-16-6, 28-17-16-7, 28-17-16-8,28-17-16-8A, 28-17-16-9, 28-17-16-10, 28-17-16-10A, 28-17-16-11,28-17-16-12, 28-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13, (10) groups 28-16-15-14-1, 28-16-15-14-2,28-16-15-14-3, 28-16-15-14-4, 28-16-15-14-5, 28-16-15-14-5A,28-16-15-14-6, 28-16-15-14-7, 28-16-15-14-8, 28-16-15-14-8A,28-16-15-14-9, 28-16-15-14-10, 28-16-15-14-10A, 28-16-15-14-11,28-16-15-14-12, 28-16-15-14-13, which are group 16 compounds in groups16-15-14-1 through 16-15-14-13, (11) groups 28-17-15-14-1,28-17-15-14-2, 28-17-15-14-3, 28-17-15-14-4, 28-17-15-14-5,28-17-15-14-5A, 28-17-15-14-6, 28-17-15-14-7, 28-17-15-14-8,28-17-15-14-8A, 28-17-15-14-9, 28-17-15-14-10, 28-17-15-14-10A,28-17-15-14-11, 28-17-15-14-12, 28-17-15-14-13, which are group 17compounds in groups 17-15-14-1 through 17-15-14-13, (12) groups28-17-16-14-1, 28-17-16-14-2, 28-17-16-14-3, 28-17-16-14-4,28-17-16-14-5, 28-17-16-14-5A, 28-17-16-14-6, 28-17-16-14-7,28-17-16-14-8, 28-17-16-14-8A, 28-17-16-14-9, 28-17-16-14-10,28-17-16-14-10A, 28-17-16-14-11, 28-17-16-14-12, 28-17-16-14-13, whichare group 17 compounds in groups 17-16-14-1 through 17-15-14-13, (13)groups 28-17-16-15-1, 28-17-16-15-2, 28-17-16-15-3, 28-17-16-15-4,28-17-16-15-5, 28-17-16-15-5A, 28-17-16-15-6, 28-17-16-15-7,28-17-16-15-8, 28-17-16-15-8A, 28-17-16-15-9, 28-17-16-15-10,28-17-16-15-10A, 28-17-16-15-11, 28-17-16-15-12 and 28-17-16-15-13,which are group 17 compounds in groups 17-16-15-1 through 17-16-15-13,(14) groups 28-17-16-15-14-1, 28-17-16-15-14-2, 28-17-16-15-14-3,28-17-16-15-14-4, 28-17-16-15-14-5, 28-17-16-15-14-5A, 28-17-16-15-14-6,28-17-16-15-14-7, 28-17-16-15-14-8, 28-17-16-15-14-8A, 28-17-16-15-14-9,28-17-16-15-14-10, 28-17-16-15-14-10A, 28-17-16-15-14-11,28-17-16-15-14-12 and 28-17-16-15-14-13, which are group 17 compounds ingroups 17-16-15-14-1 through 17-16-15-14-13, (15) all of the compoundsand/or groups described in group 18, (16) all of the compounds and/orgroups described in group 19, (17) all of the compounds and/or groupsdescribed in group 20, and (18) all of the compounds and/or groupsdescribed in groups 21, 22, 23, 24, 25, 26, 26A, 26B, 26C, 26E and 27.

Group 29. This group contains compounds in groups 1-27 above where R¹substituents 1-10 listed in Table A are replaced with the followinggroups: 1-acyl, 2-thioester, 3-thioether, 4-thioacyl, 5-epoxide,6-optionally substituted cyclopropyl, 7 —O—Si(C1-C6 alkyl)₃, 8-phosphateor a salt, e.g., Na⁺ or K⁺, 9-phosphate ester or a salt, e.g., Na⁺ orK⁺, and 10-phosphate ether or a salt, e.g., Na⁺ or K⁺. Any of thesegroups can be a moiety defined herein for that group. Thus, for Table Asubstituent 1, acyl, the R¹ group includes moieties such as —C(O)CH₃,—C(O)C₂H₅, —C(O)CH₂OH, —C(O)CH₂-halogen and —C(O)-optionally substitutedalkyl. Similarly, thioester includes moieties such as —C(O)—SCH₃,—S—C(O)-optionally substituted alkyl and —C(O)—S-optionally substitutedalkyl. The epoxide and optionally substituted cyclopropyl moieties forsubstituents 5 and 6 respectively can be at the 2-3 positions or at the3-4 positions in the α- or β-configuration.

Exemplary phosphate and phosphate esters include17β-hydroxyandrost-5-ene-3β-phosphate,17β-hydroxyandrost-5-ene-3α-phosphate,17β-hydroxy-16α-fluoroandrost-5-ene-3β-phosphate,17β-hydroxy-16α-fluoroandrost-5-ene-3α-phosphate,17β-hydroxy-5α-androstane-3β-phosphate,17β-hydroxy-5α-androstane-3α-phosphate,17β-hydroxy-5β-androstane-3β-phosphate,17β-hydroxy-5β-androstane-3α-phosphate, 17β-hydroxy-5α,14β-androstane-3β-phosphate, 17β-hydroxy-5α,14β-androstane-3α-phosphate, 17β-hydroxy-5β,14β-androstane-3β-phosphate, 17α-hydroxy-5β,14β-androstane-3β-phosphate, or a salt, 2-oxa analog, 1α-alkyl,4α-optionally substituted alkyl, 7-substituted analog, 16α-halo,16α-hydroxy, 19-nor analog or phosphate ester, e.g., phosphate methylester (—O—P(O)(O)—OCH₃), phosphate ethyl ester or phosphate optionallysubstituted alkyl ester of any of these compounds.

Group 30. This group contains compounds in groups 1-27 above where R¹substituents 1-10 listed in Table A are replaced with the followinggroups: 1-phosphate thioether, 2-thionoester, 3-amino acid, 4-peptide,5-dipeptide, 6-optionally substituted heterocycle, 7-optionallysubstituted carboxyl, 8-carbonate, 9-carbamate and 10-phosphothioester.Exemplary carbamate moieties are as described herein, e.g.,—NH—C(O)—O—CH₃, —NH—C(O)—O—C₂H₅, —NH—C(O)—O—C₃H₇, —NH—C(O)—O—C₃H₅,—NH—C(O)—O—C₄H₉, —NH—C(O)—O-optionally substituted alkyl,—NH—C(O)—O-optionally substituted heterocycle and —NH—C(O)—O-optionallysubstituted monosaccharide. Exemplary ester moieties are as describedherein, e.g., —O—C(O)—CH₃, —O—C(O)—CF₃, —O—C(O)—C₂H₅, —O——C(O)—C₃H₇, and—O—C(O)—C₄H₉. Exemplary optionally substituted carboxyl moieties aredescribed herein, including —C(O)OH or a salt, —C(O)—OCH₃, —C(O)—OC₂H₅and —C(O)—OC₃H₇. Exemplary group 30 compounds include17β-hydroxyandrost-5-ene-3β-carbamate,17β-hydroxyandrost-1,5-diene-3β-carbamate,17β-hydroxyandrost-5-ene-3α-carbamate,17α-hydroxyandrost-5-ene-3β-carbamate,17α-hydroxyandrost-5-ene-3α-carbamate,17β-hydroxyandrost-4-ene-3β-carbamate,17α-hydroxyandrost-4-ene-3β-carbamate,17α-hydroxyandrost-1,4-diene-3β-carbamate,17β-hydroxyandrost-1,5,16-triene-3-carbamate, and analogs of any ofthese compounds having one, two or more moieties such as 16α-halo,16α-fluoro, 16β-fluoro, 16-fluoro, 16α-hydroxy, 7α-hydroxy or thiol,7β-hydroxy or thiol, 7-oxo, 7α-halo, 7β-halo, 7α-fluoro, 7β-fluoro,7α-alkoxy, 7β-alkoxy, 4α-halo, 4β-halo, 4α-alkyl, 4β-alkyl, 12α-halo,12β-halo, 12α-alkyl, 12β-alkyl, 11-dihalo, 11-dialkyl, 2-oxa, 11-oxa,17-oxo, 19-nor or the like. Other moieties, e.g., amino acid andoptionally substituted heterocycle, are as described herein.

Group 31. This group contains compounds in groups 1-27 above where R¹substituents 1-10 listed in Table A are replaced with the followinggroups: 1 -thiophosphate, 2-phosphothioether, 3-thiophosphate thioether,4-phosphonoester, 5 -phosphonate, 6-phosphonate ester, 7-phosphonateether, 8-phosphonate thioether, 9 —O—S(O)(O)—OH and 10-sulfate salt,e.g., —O—S(O)(O)—O⁺Na⁻.

Group 32. This group contains compounds in groups 1-27 above where R¹substituents 1-10 listed in Table A are replaced with the followinggroups: 1-sulfate ester, e.g., —O—S(O)(O)—O—CH₃ and —O—S(O)(O)—O—C₂H₅,2-sulfate ether, 3-sulfate thioether, 4 —O—S(O)—OH, 5-sulfite salt,e.g., —O—S(O)—O⁺Na⁻, 6-sulfite ester, 7-sulfite ether, 8 -sulfoxide, 9—O—S(O)(O)—OH or a sulfate salt, e.g., —O—S(O)(O)—O⁺Na⁻, 10 —F, —Cl, —Bror —I.

Group 33. This group contains compounds in groups 1-27 above where R¹substituents 1-10 listed in Table A are replaced with the followinggroups: 1-sulfonamide, 2-sulfonamide derivative, e.g., —S(O)(O)—NHR^(PR)or —S(O)(O)—NH-optionally substituted alkyl, 3-sulfamate, 4-sulfamatederivative, e.g., —O—S(O)(O)—NHR^(PR), —O—S(O)(O)—NHCH₃,—O—S(O)(O)—NHC₂H₅, —O—S(O)(O)—NHC₃H₇, —O—S(O)(O)—NHC₄H₉,—O—S(O)(O)—N(RD)₂ or —O—S(O)(O)—NH-optionally substituted alkyl,5-sulfonate, 6-sulfamide, 7-sulfinamide, 8 -sulfurous diamide,9-optionally protected monosaccharide, e.g., D-, L- or DL-glucose,fructose, rhamnose or glucuronic acid, 10-optionally protectedoligosaccharide, e.g., D-, L- or DL-galactose-galactose,-galactose-mannose or -glucuronic acid-glucose. In this group, theoptionally protected monosaccharide and optionally protectedoligomonosaccharide moieties are typically linked to the 3-positionthrough an oxygen, sulfur or nitrogen atom.

Exemplary group 33 compounds include glycosides such as 3β-glycosidesand 3α-glycosides, 17β,16α-dihydroxyandrost-5-ene-3β-O-1′-β′-glucopyranose, 17α,16α-dihydroxyandrost-5-ene-3β-O-1′-β′-glucopyranose,17β-hydroxy-16α-fluoroandrost-5-ene-3β-O-1′-β′-glucopyranose,17β,16α-dihydroxyandrost-5-ene-3α-O-1′-β′-glucopyranose, 17α,16α-dihydroxyandrost-5-ene-3α-O-1′-β′-glucopyranose,17α-hydroxy-16β-fluoroandrost-5-ene-3α-O-1′-β′-glucopyranose and analogsof any of these compounds having one, two or more moieties describedherein for variable groups, e.g., 16α-halo, 16β-halo, 7α-hydroxy orthiol, 7β-hydroxy or thiol, 7-oxo, 7α-halo, 7β-halo, 7α-fluoro,7β-fluoro, 7α-alkoxy, 7β-alkoxy, 4α-halo, 4β-halo, 4α-alkyl, 4β-alkyl,12α-halo, 12β-halo, 12α-alkyl, 12β-alkyl, 11-dihalo, 11-alkyl,11α-alkyl, 11-dialkyl, 2-oxa, 11-oxa, 15-oxa, 17-oxo 19-nor (i.e., R⁶ is—H), 18-homo (i.e., R⁵ is —C₂H₅) or the like where any alkyl or alkoxymoieties are optionally substituted. Other exemplary moieties at R¹include β-D-glucopyranosyl, β-D-glucopyranuronosyl,β-D-2-acetamido-2-deoxy-glucopyranosyl, β-D-galactopyranosyl,β-D-fucopyranosyl, β-L-fucopyranosyl, α-D-fructofuranosyl,β-D-fructofuranosyl, β-D-xylopyranosyl, β-L-xylopyranosyl,α-D-arabanopyranosyl, α-L-arabanopyranosyl, α-L-rhamnopyranosyl,α-D-rhamnopyranosyl, α-D-cellobiosyl, β-D-cellobiosyl, β-D-lactosyl,β-D-maltosyl, β-D-gentiobiosyl,3-O-β-D-galactopyranosyl-α-D-arabanopyranosyl and β-D-maltotriosylmoieties, any of which are optionally protected and where R¹ is in theα- or β-configuration.

These compounds include compounds in group 33-1 through33-27-20-19-18-17-16-15-14-13, which collectively are group 33compounds. These include groups 33-1, 33-2, 33-3, 33-4, 33-5, 33-5A,33-6, 33-7, 33-8, 33-8A, 33-9, 33-10, 33-10A, 33-11, 33-12, 33-13, whichare compounds in groups 1 through 13 where R¹ substituents 1-10 in TableA are replaced with the moieties given in this group. Group 33 compoundsalso include groups 33-14-1, 33-14-2, 33-14-3, 33-14-4, 33-14-5,33-14-5A, 33-14-6, 33-14-7, 33-14-8, 33-14-8A, 33-14-9, 33-14-10,33-14-10A, 33-14-11, 33-14-12 and 33-14-13, which are group 14 compoundsin groups 14-1 through 14-13 where R¹ substituents 1-10 in Table A arereplaced with the moieties given in this group.

Other group 33 compounds include (1) groups 33-15-1, 33-15-2, 33-15-3,33-15-4, 33-15-5, 33-15-5A, 33-15-6, 33-15-7, 33-15-8, 33-15-8A,33-15-9, 33-15-10, 33-15-10A, 33-15-11, 33-15-12 and 33-15-13, which aregroup 15 compounds in groups 15-1 through 15-13, (2) groups 33-16-1,33-16-2, 33-16-3, 33-16-4, 33-16-5, 33-16-5A, 33-16-6, 33-16-7, 33-16-8,33-16-8A, 33-16-9, 33-16-10, 33-16-10A, 33-16-11, 33-16-12 and 33-16-13,which are group 16 compounds in groups 16-1 through 16-13, (3) groups33-17-1, 33-17-2, 33-17-3, 33-17-4, 33-17-5, 33-17-5A, 33-17-6, 33-17-7,33-17-8, 33-17-8A, 33-17-9, 33-17-10, 33-17-10A, 33-17-11, 33-17-12 and33-17-13, which are group 17 compounds in groups 17-1 through 17-13, (4)groups 33-15-14-1, 33-15-14-2, 33-15-14-3, 33-15-14-4, 33-15-14-5,33-15-14-5A, 33-15-14-6, 33-15-14-7, 33-15-14-8, 33-15-14-8A,33-15-14-9, 33-15-14-10, 33-15-14-10A, 33-15-14-11, 33-15-14-12 and33-15-14-13, which are group 15 compounds in groups 15-14-1 through15-14-13, (5) groups 33-16-14-1, 33-16-14-2, 33-16-14-3, 33-16-14-4,33-16-14-5, 33-16-14-5A, 33-16-14-6, 33-16-14-7, 33-16-14-8,33-16-14-8A, 33-16-14-9, 33-16-14-10, 33-16-14-10A, 33-16-14-11,33-16-14-12 and 33-16-14-13, which are group 16 compounds in groups16-14-1 through 16-14-13, (6) groups 33-17-14-1, 33-17-14-2, 33-17-14-3,33-17-14-4, 33-17-14-5, 33-17-14-5A, 33-17-14-6, 33-17-14-7, 33-17-14-8,33-17-14-8A, 33-17-14-9, 33-17-14-10, 33-17-14-10A, 33-17-14-11,33-17-14-12, 33-17-14-13, which are group 17 compounds in groups 17-14-1through 17-14-13, (7) groups 33-16-15-1, 33-16-15-2, 33-16-15-3,33-16-15-4, 33-16-15-5, 33-16-15-5A, 33-16-15-6, 33-16-15-7, 33-16-15-8,33-16-15-8A, 33-16-15-9, 33-16-15-10, 33-16-15-10A, 33-16-15-11,33-16-15-12, 33-16-15-13, which are group 16 compounds in groups 16-15-1through 16-15-13, (8) groups 33-17-15-1, 33-17-15-2, 33-17-15-3,33-17-15-4, 33-17-15-5, 33-17-15-5A, 33-17-15-6, 33-17-15-7, 33-17-15-8,33-17-15-8A, 33-17-15-9, 33-17-15-10, 33-17-15-10A, 33-17-15-11,33-17-15-12, 33-17-15-13, which are group 17 compounds in groups 17-15-1through 17-15-13, (9) groups 33-17-16-1, 33-17-16-2, 33-17-16-3,33-17-16-4, 33-17-16-5, 33-17-16-5A, 33-17-16-6, 33-17-16-7, 33-17-16-8,33-17-16-8A, 33-17-16-9, 33-17-16-10, 33-17-16-10A, 33-17-16-11,33-17-16-12, 33-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13, (10) groups 33-16-15-14-1, 33-16-15-14-2,33-16-15-14-3, 33-16-15-14-4, 33-16-15-14-5, 33-16-15-14-5A,33-16-15-14-6, 33-16-15-14-7, 33-16-15-14-8, 33-16-15-14-8A,33-16-15-14-9, 33-16-15-14-10, 33-16-15-14-10A, 33-16-15-14-11,33-16-15-14-12, 33-16-15-14-13, which are group 16 compounds in groups16-15-14-1 through 16-15-14-13, (11) groups 33-17-15-14-1,33-17-15-14-2, 33-17-15-14-3, 33-17-15-14-4, 33-17-15-14-5,33-17-15-14-5A, 33-17-15-14-6, 33-17-15-14-7, 33-17-15-14-8,33-17-15-14-8A, 33-17-15-14-9, 33-17-15-14-10, 33-17-15-14-10A,33-17-15-14-11, 33-17-15-14-12, 33-17-15-14-13, which are group 17compounds in groups 17-15-14-1 through 17-15-14-13, (12) groups33-17-16-14-1, 33-17-16-14-2, 33-17-16-14-3, 33-17-16-14-4,33-17-16-14-5, 33-17-16-14-5A, 33-17-16-14-6, 33-17-16-14-7,33-17-16-14-8, 33-17-16-14-8A, 33-17-16-14-9, 33-17-16-14-10,33-17-16-14-10A, 33-17-16-14-11, 33-17-16-14-12, 33-17-16-14-13, whichare group 17 compounds in groups 17-16-14-1 through 17-15-14-13, (13)groups 33-17-16-15-1, 33-17-16-15-2, 33-17-16-15-3, 33-17-16-15-4,33-17-16-15-5, 33-17-16-15-5A, 33-17-16-15-6, 33-17-16-15-7,33-17-16-15-8, 33-17-16-15-8A, 33-17-16-15-9, 33-17-16-15-10,33-17-16-15-10A, 33-17-16-15-11, 33-17-16-15-12 and 33-17-16-15-13,which are group 17 compounds in groups 17-16-15-1 through 17-16-15-13,(14) groups 33-17-16-15-14-1, 33-17-16-15-14-2, 33-17-16-15-14-3,33-17-16-15-14-4, 33-17-16-15-14-5, 33-17-16-15-14-5A, 33-17-16-15-14-6,33-17-16-15-14-7, 33-17-16-15-14-8, 33-17-16-15-14-8A, 33-17-16-15-14-9,33-17-16-15-14-10, 33-17-16-15-14-10A, 33-17-16-15-14-11,33-17-16-15-14-12 and 33-17-16-15-14-13, which are group 17 compounds ingroups 17-16-15-14-1 through 17-16-15-14-13, (15) all of the compoundsand/or groups described in group 18, (16) all of the compounds and/orgroups described in group 19, (17) all of the compounds and/or groupsdescribed in group 20, and (18) all of the compounds and/or groupsdescribed in groups 21, 22, 23, 24, 25, 26, 26A, 26B, 26C, 26E and 27.

Group 33A. This group contains compounds in groups 1-27 above where R¹substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —N-pyrrolidine, 2 —N1-pyrazolone, 3 —N2-pyrazolone, 4—N-imidazolidin-2-one, 5 —N1-imidazole, 6 —N1-4,5-dihydroimidazole, 7—N-morpholine, 8 —N1-pyridine, 9 —N-piperidine, 10 —N-piperazine. Asexamples, group 33A-3 compound 1.1.6.9 (i.e., group 33A compound 1.1.6.9from group 3) is 3β-N-pyrrolidinyl-16α, 17β-dihydroxyandrost-5-ene and33A-3 compound 1.1.4.9 is3β-N-pyrrolidinyl-16α-fluoro-17β-hydroxyandrost-5-ene, group 33A-4compound 1.1.6.9 (i.e., group 26A compound 1.1.6.9 from group 4) is3β-N-pyrrolidinyl-16α, 17β-dihydroxyandrost-1,5-diene and 26A-4 compound1.1.4.9 is 3β-N-pyrrolidinyl-16α-fluoro-17β-hydroxyandrost-1,5-diene.

These compounds include compounds in group 33A-1 through33A-27-20-19-18-17-16-15-14-13, which collectively are group 33Acompounds. These include groups 33A-1, 33A-2, 33A-3, 33A-4, 33A-5,33A-5A, 33A-6, 33A-7, 33A-8, 33A-8A, 33A-9, 33A-10, 33A-10A, 33A-11,33A-12, 33A-13, which are compounds in groups 1 through 13 where R¹substituents 1-10 in Table A are replaced with the moieties given inthis group. Group 33A compounds also include groups 33A-14-1, 33A-14-2,33A-14-3, 33A-14-4, 33A-14-5, 33A-14-5A, 33A-14-6, 33A-14-7, 33A-14-8,33A-14-8A, 33A-14-9, 33A-14-10, 33A-14-10A, 33A-14-11, 33A-14-12 and33A-14-13, which are group 14 compounds in groups 14-1 through 14-13where R¹ substituents 1-10 in Table A are replaced with the moietiesgiven in this group.

Other group 33A compounds include (1) groups 33A-15-1, 33A-15-2,33A-15-3, 33A-15-4, 33A-15-5, 33A-15-5A, 33A-15-6, 33A-15-7, 33A-15-8,33A-15-8A, 33A-15-9, 33A-15-10, 33A-15-10A, 33A-15-11, 33A-15-12 and33A-15-13, which are group 15 compounds in groups 15-1 through 15-13,(2) groups 33A-16-1, 33A-16-2, 33A-16-3, 33A-16-4, 33A-16-5, 33A-16-5A,33A-16-6, 33A-16-7, 33A-16-8, 33A-16-8A, 33A-16-9, 33A-16-10,33A-16-10A, 33A-16-11, 33A-16-12 and 33A-16-13, which are group 16compounds in groups 16-1 through 16-13, (3) groups 33A-17-1, 33A-17-2,33A-17-3, 33A-17-4, 33A-17-5, 33A-17-5A, 33A-17-6, 33A-17-7, 33A-17-8,33A-17-8A, 33A-17-9, 33A-17-10, 33A-17-10A, 33A-17-11, 33A-17-12 and33A-17-13, which are group 17 compounds in groups 17-1 through 17-13,(4) groups 33A-15-14-1, 33A-15-14-2, 33A-15-14-3, 33A-15-14-4,33A-15-14-5, 33A-15-14-5A, 33A-15-14-6, 33A-15-14-7, 33A-15-14-8,33A-15-14-8A, 33A-15-14-9, 33A-15-14-10, 33A-15-14-10A, 33A-15-14-11,33A-15-14-12 and 33A-15-14-13, which are group 15 compounds in groups15-14-1 through 15-14-13, (5) groups 33A-16-14-1, 33A-16-14-2,33A-16-14-3, 33A-16-14-4, 33A-16-14-5, 33A-16-14-5A, 33A-16-14-6,33A-16-14-7, 33A-16-14-8, 33A-16-14-8A, 33A-16-14-9, 33A-16-14-10,33A-16-14-10A, 33A-16-14-11, 33A-16-14-12 and 33A-16-14-13, which aregroup 16 compounds in groups 16-14-1 through 16-14-13, (6) groups33A-17-14-1, 33A-17-14-2, 33A-17-14-3, 33A-17-14-4, 33A-17-14-5,33A-17-14-5A, 33A-17-14-6, 33A-17-14-7, 33A-17-14-8, 33A-17-14-8A,33A-17-14-9, 33A-17-14-10, 33A-17-14-10A, 33A-17-14-11, 33A-17-14-12,33A-17-14-13, which are group 17 compounds in groups 17-14-1 through17-14-13, (7) groups 33A-16-15-1, 33A-16-15-2, 33A-16-15-3, 33A-16-15-4,33A-16-15-5, 33A-16-15-5A, 33A-16-15-6, 33A-16-15-7, 33A-16-15-8,33A-16-15-8A, 33A-16-15-9, 33A-16-15-10, 33A-16-15-10A, 33A-16-15-11,33A-16-15-12, 33A-16-15-13, which are group 16 compounds in groups16-15-1 through 16-15-13, (8) groups 33A-17-15-1, 33A-17-15-2,33A-17-15-3, 33A-17-15-4, 33A-17-15-5, 33A-17-15-5A, 33A-17-15-6,33A-17-15-7, 33A-17-15-8, 33A-17-15-8A, 33A-17-15-9, 33A-17-15-10,33A-17-15-10A, 33A-17-15-11, 33A-17-15-12, 33A-17-15-13, which are group17 compounds in groups 17-15-1 through 17-15-13, (9) groups 33A-17-16-1,33A-17-16-2, 33A-17-16-3, 33A-17-16-4, 33A-17-16-5, 33A-17-16-5A,33A-17-16-6, 33A-17-16-7, 33A-17-16-8, 33A-17-16-8A, 33A-17-16-9,33A-17-16-10, 33A-17-16-10A, 33A-17-16-11, 33A-17-16-12, 33A-17-16-13,which are group 17 compounds in groups 17-16-1 through 17-16-13, (10)groups 33A-16-15-14-1, 33A-16-15-14-2, 33A-16-15-14-3, 33A-16-15-14-4,33A-16-15-14-5, 33A-16-15-14-5A, 33A-16-15-14-6, 33A-16-15-14-7,33A-16-15-14-8, 33A-16-15-14-8A, 33A-16-15-14-9, 33A-16-15-14-10,33A-16-15-14-10A, 33A-16-15-14-11, 33A-16-15-14-12, 33A-16-15-14-13,which are group 16 compounds in groups 16-15-14-1 through 16-15-14-13,(11) groups 33A-17-15-14-1, 33A-17-15-14-2, 33A-17-15-14-3,33A-17-15-14-4, 33A-17-15-14-5, 33A-17-15-14-5A, 33A-17-15-14-6,33A-17-15-14-7, 33A-17-15-14-8, 33A-17-15-14-8A, 33A-17-15-14-9,33A-17-15-14-10, 33A-17-15-14-10A, 33A-17-15-14-11, 33A-17-15-14-12,33A-17-15-14-13, which are group 17 compounds in groups 17-15-14-1through 17-15-14-13, (12) groups 33A-17-16-14-1, 33A-17-16-14-2,33A-17-16-14-3, 33A-17-16-14-4, 33A-17-16-14-5, 33A-17-16-14-5A,33A-17-16-14-6, 33A-17-16-14-7, 33A-17-16-14-8, 33A-17-16-14-8A,33A-17-16-14-9, 33A-17-16-14-10, 33A-17-16-14-10A, 33A-17-16-14-11,33A-17-16-14-12, 33A-17-16-14-13, which are group 17 compounds in groups17-16-14-1 through 17-15-14-13, (13) groups 33A-17-16-15-1,33A-17-16-15-2, 33A-17-16-15-3, 33A-17-16-15-4, 33A-17-16-15-5,33A-17-16-15-5A, 33A-17-16-15-6, 33A-17-16-15-7, 33A-17-16-15-8,33A-17-16-15-8A, 33A-17-16-15-9, 33A-17-16-15-10, 33A-17-16-15-10A,33A-17-16-15-11, 33A-17-16-15-12 and 33A-17-16-15-13, which are group 17compounds in groups 17-16-15-1 through 17-16-15-13, (14) groups33A-17-16-15-14-1, 33A-17-16-15-14-2, 33A-17-16-15-14-3,33A-17-16-15-14-4, 33A-17-16-15-14-5, 33A-17-16-15-14-5A,33A-17-16-15-14-6, 33A-17-16-15-14-7, 33A-17-16-15-14-8,33A-17-16-15-14-8A, 33A-17-16-15-14-9, 33A-17-16-15-14-10,33A-17-16-15-14-10A, 33A-17-16-15-14-11, 33A-17-16-15-14-12 and33A-17-16-15-14-13, which are group 17 compounds in groups 17-16-15-14-1through 17-16-15-14-13, (15) all of the compounds and/or groupsdescribed in group 18, (16) all of the compounds and/or groups describedin group 19, (17) all of the compounds and/or groups described in group20, and (18) all of the compounds and/or groups described in groups 21,22, 23, 24, 25, 26, 26A, 26B, 26C, 26E and 27.

Group 33B. This group contains compounds in groups 1-27 above where R¹substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —N-piperazine substituted at N4 with optionally substitutedalkyl, 2 —N-indole, 3 —N-indoline, 4 —N-quinolidine, 5—NH—C(O)—CH₂—CH₂—C(O)—OH, 6 —NH—C(O)—CH₂—C(O)—OH, 7—NH—C(O)—CH₂—CH₂—C(O)—OR^(PR), 8 —NH—C(O)—CH₂—C(O)—OR^(PR), 9—NH—C(O)—(CH₂)₃—C(O)—OH, 10 —NH—C(O)—(CH₂)₃—C(O)—OR^(PR). Ionizablemoieties such as free carboxyl groups include salts, e.g., Na⁺ or K⁺.R^(PR) is a protecting group.

Group 33C. This group contains compounds in groups 1-27 above where R¹substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —NH—CH(CH₃)—C(O)OH, 2 —NH—CH(CH₃)—C(O)OR^(PR), 3—NH—CH(CH₂OH)—C(O)OH, 4 —NH—CH(CH₂OH)—C(O)OR^(PR), 5—NH—CH₂—CH₂—C(O)—OH, 6 —NH—CH₂—C(O)—OH, 7 —NH—CH₂—CH₂—C(O)—OR^(PR), 8—NH—CH₂—C(O)—OR^(PR), 9 —NH—(CH₂)₃—C(O)—OH, 10 —NH—(CH₂)₃—C(O)—OR^(PR).Ionizable moieties such as free carboxyl groups include salts, e.g., Na⁺or K⁺. R^(PR) is a protecting group.

Group 33D. This group contains compounds in groups 1-27 above where R¹substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —NH—CH(CH₃)—C(O)OH, 2 —NH—NH—C(O)CH₃, 3 —NH—NH—C(O)OCH₃, 4—NH—NH—C(O)C₂H₅, 5 —NH—NH—C(O)OC₂H₅, 6 —NH—NH—C(O)C₃H₇, 7—NH—NH—C(O)-optionally substituted alkyl, 8 —NH—C(NH-optionallysubstituted alkyl)=N-optionally substituted alkyl, 9—NH—C(NH—CH₃)═N—CH₃, 10 —NH—C(NH—C₂H₅)═N—C₂H₅.

Group 33E. This group contains compounds in groups 1-27 above where R¹substituents 1-10 listed in Table A are replaced with the followinggroups: 1 spiro β-NH—(CH₂)₂—O-α, 2 spiro α-NH—(CH₂)₂—O-β, 3 spiroβ-NH—(CH₂)₂—NH-α, 4 spiro α-NH—(CH₂)₂—NH-β, 5 spiro β-NH—CH═N—CH₂-α, 6spiro α-NH—CH═N—CH₂-β, 7 spiro β-NH—CHR¹⁰—CHR¹⁰—O-α, 8 spiroα-NH—CHR¹⁰—CHR¹⁰—O-β, 9 spiro β-NH—CHR¹⁰—CHR¹⁰—NH-α, 10 spiroα-NH—CHR¹⁰—CHR¹⁰—NH-β. Each R¹⁰ is independently chosen and has themeaning given above, e.g., —H, —OH, ═O, —SH, ═S, halogen or optionallysubstituted alkyl.

Group 34. This group contains compounds in groups 1-27 above where R¹substituents 1-10 listed in Table A are replaced with the followinggroups: 1-glycol, e.g., propylene glycol or ethylene glycol,2-polyethylene glycol, e.g., PEG 100 or PEG 200, 3 -an acetal ring, 4-aspiro ring, 5-a thioacetal ring, 6 spiro —O—CH₂—O—, 7 spiro—O—(CH₂)₂—O—, 8 spiro —NH—(CH₂)₂—O—, 9 —NH—C(O)—(CH₂)₂—C(O)O—CH₃, 10—NH—C(O)—(CH₂)₂—C(O)—OH.

Group 35. This group contains compounds in groups 1-34 above where R³substituents 1-10 listed in Table A are replaced with the followinggroups: 1-optionally substituted amine, 2-optionally substituted amide,3-optionally substituted oxime, 4 -optionally substituted alkyl,5-optionally substituted alkenyl, 6-optionally substituted alkynyl,7-optionally substituted aryl, 8-optionally substituted heterocycle,9-ether and 10-ester. Any of these groups can be a moiety defined ordescribed herein for that moiety, e.g., optionally substituted amineincludes —NH₂, —NH₃ ⁺Cl⁻, —NH₃ ⁺Br⁻, —NH₃ ⁺I⁻, —NHCH₃, —N(CH₃)₂,—NHC₂H₅, —N(C₂H₅)₂, —NHC₃H₇, —N(C₃H₇)₂, —NHC₄H₉, —N(C₄H₉)₂,—NH-optionally substituted alkyl, —N(optionally substituted alkyl)₂,—NH—C₆H₅, —N(C₆H₅)₂, —NH-optionally substituted monosaccharide and—NH-optionally substituted oligosaccharide, and optionally substitutedamide includes —NHC(O)-optionally substituted alkyl,—N(CH₃)—C(O)-optionally substituted alkyl, —N(C₂H₅)—C(O)-optionallysubstituted alkyl, —N(C₃H₇)—C(O)-optionally substituted alkyl,—N(C₄H₉)—C(O)-optionally substituted alkyl, —N(C₆H₅)—C(O)-optionallysubstituted alkyl, —NH—C(O)-optionally substituted monosaccharide and—NH—C(O)-optionally substituted oligosaccharide, where alkyl or phenylgroups are the same or different and are optionally substituted asdescribed herein.

These compounds include compounds in group 35-1 through35-34-27-20-19-18-17-16-15-14-13, which collectively are group 35compounds. These include groups 35-1, 35-2, 35-3, 35-4, 35-5, 35-5A,35-6, 35-7, 35-8, 35-8A, 35-9, 35-10, 35-10A, 35-11, 35-12, 35-13, whichare compounds in groups 1 through 13 where R³ substituents 1-10 in TableA are replaced with the moieties given in this group. Group 35 compoundsalso include groups 35-14-1, 35-14-2, 35-14-3, 35-14-4, 35-14-5,35-14-5A, 35-14-6, 35-14-7, 35-14-8, 35-14-8A, 35-14-9, 35-14-10,35-14-10A, 35-14-11, 35-14-12 and 35-14-13, which are group 14 compoundsin groups 14-1 through 14-13 where R³ substituents 1-10 in Table A arereplaced with the moieties given in this group.

Other group 35 compounds include (1) groups 35-15-1, 35-15-2, 35-15-3,35-15-4, 35-15-5, 35-15-5A, 35-15-6, 35-15-7, 35-15-8, 35-15-8A,35-15-9, 35-15-10, 35-15-10A, 35-15-11, 35-15-12 and 35-15-13, which aregroup 15 compounds in groups 15-1 through 15-13, (2) groups 35-16-1,35-16-2, 35-16-3, 35-16-4, 35-16-5, 35-16-5A, 35-16-6, 35-16-7, 35-16-8,35-16-8A, 35-16-9, 35-16-10, 35-16-10A, 35-16-11, 35-16-12 and 35-16-13,which are group 16 compounds in groups 16-1 through 16-13, (3) groups35-17-1, 35-17-2, 35-17-3, 35-17-4, 35-17-5, 35-17-5A, 35-17-6, 35-17-7,35-17-8, 35-17-8A, 35-17-9, 35-17-10, 35-17-10A, 35-17-11, 35-17-12 and35-17-13, which are group 17 compounds in groups 17-1 through 17-13, (4)groups 35-15-14-1, 35-15-14-2, 35-15-14-3, 35-15-14-4, 35-15-14-5,35-15-14-5A, 35-15-14-6, 35-15-14-7, 35-15-14-8, 35-15-14-8A,35-15-14-9, 35-15-14-10, 35-15-14-10A, 35-15-14-11, 35-15-14-12 and35-15-14-13, which are group 15 compounds in groups 15-14-1 through15-14-13, (5) groups 35-16-14-1, 35-16-14-2, 35-16-14-3, 35-16-14-4,35-16-14-5, 35-16-14-5A, 35-16-14-6, 35-16-14-7, 35-16-14-8,35-16-14-8A, 35-16-14-9, 35-16-14-10, 35-16-14-10A, 35-16-14-11,35-16-14-12 and 35-16-14-13, which are group 16 compounds in groups16-14-1 through 16-14-13, (6) groups 35-17-14-1, 35-17-14-2, 35-17-14-3,35-17-14-4, 35-17-14-5, 35-17-14-5A, 35-17-14-6, 35-17-14-7, 35-17-14-8,35-17-14-8A, 35-17-14-9, 35-17-14-10, 35-17-14-10A, 35-17-14-11,35-17-14-12, 35-17-14-13, which are group 17 compounds in groups 17-14-1through 17-14-13, (7) groups 35-16-15-1, 35-16-15-2, 35-16-15-3,35-16-15-4, 35-16-15-5, 35-16-15-5A, 35-16-15-6, 35-16-15-7, 35-16-15-8,35-16-15-8A, 35-16-15-9, 35-16-15-10, 35-16-15-10A, 35-16-15-11,35-16-15-12, 35-16-15-13, which are group 16 compounds in groups 16-15-1through 16-15-13, (8) groups 35-17-15-1, 35-17-15-2, 35-17-15-3,35-17-15-4, 35-17-15-5, 35-17-15-5A, 35-17-15-6, 35-17-15-7, 35-17-15-8,35-17-15-8A, 35-17-15-9, 35-17-15-10, 35-17-15-10A, 35-17-15-11,35-17-15-12, 35-17-15-13, which are group 17 compounds in groups 17-15-1through 17-15-13, (9) groups 35-17-16-1, 35-17-16-2, 35-17-16-3,35-17-16-4, 35-17-16-5, 35-17-16-5A, 35-17-16-6, 35-17-16-7, 35-17-16-8,35-17-16-8A, 35-17-16-9, 35-17-16-10, 35-17-16-10A, 35-17-16-11,35-17-16-12, 35-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13, (10) groups 35-16-15-14-1, 35-16-15-14-2,35-16-15-14-3, 35-16-15-14-4, 35-16-15-14-5, 35-16-15-14-5A,35-16-15-14-6, 35-16-15-14-7, 35-16-15-14-8, 35-16-15-14-8A,35-16-15-14-9, 35-16-15-14-10, 35-16-15-14-10A, 35-16-15-14-11,35-16-15-14-12, 35-16-15-14-13, which are group 16 compounds in groups16-15-14-1 through 16-15-14-13, (11) groups 35-17-15-14-1,35-17-15-14-2, 35-17-15-14-3, 35-17-15-14-4, 35-17-15-14-5,35-17-15-14-5A, 35-17-15-14-6, 35-17-15-14-7, 35-17-15-14-8,35-17-15-14-8A, 35-17-15-14-9, 35-17-15-14-10, 35-17-15-14-10A,35-17-15-14-11, 35-17-15-14-12, 35-17-15-14-13, which are group 17compounds in groups 17-15-14-1 through 17-15-14-13, (12) groups35-17-16-14-1, 35-17-16-14-2, 35-17-16-14-3, 35-17-16-14-4,35-17-16-14-5, 35-17-16-14-5A, 35-17-16-14-6, 35-17-16-14-7,35-17-16-14-8, 35-17-16-14-8A, 35-17-16-14-9, 35-17-16-14-10,35-17-16-14-10A, 35-17-16-14-11, 35-17-16-14-12, 35-17-16-14-13, whichare group 17 compounds in groups 17-16-14-1 through 17-15-14-13, (13)groups 35-17-16-15-1, 35-17-16-15-2, 35-17-16-15-3, 35-17-16-15-4,35-17-16-15-5, 35-17-16-15-5A, 35-17-16-15-6, 35-17-16-15-7,35-17-16-15-8, 35-17-16-15-8A, 35-17-16-15-9, 35-17-16-15-10,35-17-16-15-10A, 35-17-16-15-11, 35-17-16-15-12 and 35-17-16-15-13,which are group 17 compounds in groups 17-16-15-1 through 17-16-15-13,(14) groups 35-17-16-15-14-1, 35-17-16-15-14-2, 35-17-16-15-14-3,35-17-16-15-14-4, 35-17-16-15-14-5, 35-17-16-15-14-5A, 35-17-16-15-14-6,35-17-16-15-14-7, 35-17-16-15-14-8, 35-17-16-15-14-8A, 35-17-16-15-14-9,35-17-16-15-14-10, 35-17-16-15-14-10A, 35-17-16-15-14-11,35-17-16-15-14-12 and 35-17-16-15-14-13, which are group 17 compounds ingroups 17-16-15-14-1 through 17-16-15-14-13, (15) all of the compoundsand/or groups described in group 18, (16) all of the compounds and/orgroups described in group 19, (17) all of the compounds and/or groupsdescribed in group 20, (18) all of the compounds and/or groups describedin groups 21, 22, 23, 24, 25, 26, 26A, 26B, 26C, 26E and 27, (19) all ofthe compounds and/or groups described in groups 28, 29, 30, 31, 32, 33,33A, 33B, 33C, 33D, 33E and 34 and (20) all of the compounds and/orgroups described in groups 35, 36, 37, 38, 39, 40, 40A, 40B, 40C, 40D,40E and 41.

Group 36. This group contains compounds in groups 1-34 above where R³substituents 1-10 listed in Table A are replaced with the followinggroups: 1-acyl, 2 -thioester, 3-thioether, 4-thioacyl, 5-epoxide,6-optionally substituted cyclopropyl, 7 —O—Si(C1-C6 alkyl)₃,8-phosphate, 9-phosphate ester and 10-phosphate ether. Any of thesegroups can be a moiety defined herein for that group. The epoxide andoptionally substituted cyclopropyl moieties for substituents 5 and 6respectively can be at the 15-16 positions or at the 16-17 positions inthe α- or β-configuration.

Group 37. This group contains compounds in groups 1-34 above where R³substituents 1-10 listed in Table A are replaced with the followinggroups: 1-phosphate thioether, 2-thionoester, 3-amino acid, 4-peptide,5-dipeptide, 6-optionally substituted heterocycle, 7-optionallysubstituted carboxyl, 8-carbonate, 9-carbamate and 10-phosphothioester.

Group 38. This group contains compounds in groups 1-34 above where R³substituents 1-10 listed in Table A are replaced with the followinggroups: 1 -thiophosphate, 2-phosphothioether, 3-thiophosphate thioether,4-phosphonoester, 5 -phosphonate, 6-phosphonate ester, 7-phosphonateether, 8-phosphonate thioether, 9 —O—S(O)(O)—OH and 10-sulfate salt,e.g., —O—S(O)(O)—O⁺Na⁻.

Group 39. This group contains compounds in groups 1-34 above where R³substituents 1-10 listed in Table A are replaced with the followinggroups: 1-sulfate ester, 2-sulfate ether, 3-sulfate thioether, 4—O—S(O)—OH, 5-sulfite salt, e.g., —O—S(O)—O⁺Na⁻, 6 -sulfite ester,7-sulfite ether, 8-sulfoxide, 9 —O—S(O)(O)—OR^(PR) and 10—O—S(O)(O)—OCH₃.

Group 40. This group contains compounds in groups 1-34 above where R³substituents 1-10 listed in Table A are replaced with the followinggroups: 1-sulfonamide, 2-sulfonamide derivative, e.g., —S(O)(O)—NHR^(PR)or —S(O)(O)—NH-optionally substituted alkyl, 3-sulfamate, 4-sulfamatederivative, e.g., —O—S(O)(O)—NHR^(PR), —O—S(O)(O)—NHCH₃,—O—S(O)(O)—NHC₂H₅, —O—S(O)(O)—NHC₃H₇, —O—S(O)(O)—NHC₄H₉,—O—S(O)(O)—N(RD)₂ or —O—S(O)(O)—NH-optionally substituted alkyl,5-sulfonate, 6-sulfamide, 7-sulfinamide, 8 -sulfurous diamide,9-optionally protected monosaccharide, e.g., D-, L- or DL-glucose,fructose, rhamnose or glucuronic acid, 10-optionally protectedoligosaccharide, e.g., D-, L- or DL-galactose-galactose,-galactose-mannose or -glucuronic acid-glucose. In this group, theoptionally protected monosaccharide and optionally protectedoligomonosaccharide moieties are typically linked to the 3-positionthrough an oxygen, sulfur or nitrogen atom.

Exemplary group 40 compounds include glycosides such as 16β-glycosidesand 16α-glycosides, 3β,17β-dihydroxyandrost-5-ene-16α-O-1′-β′-glucopyranose, 3α,17β-dihydroxyandrost-5-ene-16β-O-1′-β′-glucopyranose,3β-hydroxy-17-oxoandrost-5-ene-16β-O-1′-β′-glucopyranose, 3β,17α-dihydroxyandrost-5-ene-16α-1′-β′-glucopyranose, 3α,17α-dihydroxyandrost-5-ene-16β-O-1′-β′-glucopyranose,3β-hydroxy-74-fluoro-17-oxoandrost-5-ene-17α-1′-β′-glucopyranose andanalogs of any of these compounds having one, two or more moietiesdescribed herein for variable groups, e.g., 16α-halo, 16β-halo,7α-hydroxy or thiol, 7β-hydroxy or thiol, 7-oxo, 7α-halo, 7β-halo,7α-fluoro, 7β-fluoro, 7α-alkoxy, 7β-alkoxy, 4α-halo, 4β-halo, 4α-alkyl,4β-alkyl, 12α-halo, 12β-halo, 12-dialkyl, 12α-alkyl, 12β-alkyl,11-dihalo, 11-alkyl, 11α-alkyl, 11-dialkyl, 2-oxa, 11-oxa, 15-oxa,19-nor (i.e., R⁶ is —H), 18-homo (i.e., R⁵ is —C₂H₅) or the like whereany alkyl or alkoxy moieties are optionally substituted. Other exemplarymoieties at R³ include β-D-glucopyranosyl, β-D-glucopyranuronosyl,β-D-2-acetamido-2-deoxy-glucopyranosyl, β-D-galactopyranosyl,β-D-fucopyranosyl, β-L-fucopyranosyl, α-D-fructofuranosyl,β-D-fructofuranosyl, β-D-xylopyranosyl, β-L-xylopyranosyl,α-D-arabanopyranosyl, α-L-arabanopyranosyl, α-L-rhamnopyranosyl,α-D-rhamnopyranosyl, α-D-cellobiosyl, β-D-cellobiosyl, β-D-lactosyl,β-D-maltosyl, β-D-gentiobiosyl,3-O-β-D-galactopyranosyl-α-D-arabanopyranosyl or β-D-maltotriosyl, anyof which are optionally protected and where R³ is in the α- orβ-configuration.

These compounds include compounds in group 40-1 through40-41-34-27-20-19-18-17-16-15-14-13, which collectively are group 40compounds. These include groups 40-1, 40-2, 40-3, 40-4, 40-5, 40-5A,40-6, 40-7, 40-8, 40-8A, 40-9, 40-10, 40-10A, 40-11, 40-12, 40-13, whichare compounds in groups 1 through 13 where R³ substituents 1-10 in TableA are replaced with the moieties given in this group. Group 40 compoundsalso include groups 40-14-1, 40-14-2, 40-14-3, 40-14-4, 40-14-5,40-14-5A, 40-14-6, 40-14-7, 40-14-8, 40-14-8A, 40-14-9, 40-14-10,40-14-10A, 40-14-11, 40-14-12 and 40-14-13, which are group 14 compoundsin groups 14-1 through 14-13 where R³ substituents 1-10 in Table A arereplaced with the moieties given in this group.

Other group 40 compounds include (1) groups 40-15-1, 40-15-2, 40-15-3,40-15-4, 40-15-5, 40-15-5A, 40-15-6, 40-15-7, 40-15-8, 40-15-8A,40-15-9, 40-15-10, 40-15-10A, 40-15-11, 40-15-12 and 40-15-13, which aregroup 15 compounds in groups 15-1 through 15-13, (2) groups 40-16-1,40-16-2, 40-16-3, 40-16-4, 40-16-5, 40-16-5A, 40-16-6, 40-16-7, 40-16-8,40-16-8A, 40-16-9, 40-16-10, 40-16-10A, 40-16-11, 40-16-12 and 40-16-13,which are group 16 compounds in groups 16-1 through 16-13, (3) groups40-17-1, 40-17-2, 40-17-3, 40-17-4, 40-17-5, 40-17-5A, 40-17-6, 40-17-7,40-17-8, 40-17-8A, 40-17-9, 40-17-10, 40-17-10A, 40-17-11, 40-17-12 and40-17-13, which are group 17 compounds in groups 17-1 through 17-13, (4)groups 40-15-14-1, 40-15-14-2, 40-15-14-3, 40-15-14-4, 40-15-14-5,40-15-14-5A, 40-15-14-6, 40-15-14-7, 40-15-14-8, 40-15-14-8A,40-15-14-9, 40-15-14-10, 40-15-14-10A, 40-15-14-11, 40-15-14-12 and40-15-14-13, which are group 15 compounds in groups 15-14-1 through15-14-13, (5) groups 40-16-14-1, 40-16-14-2, 40-16-14-3, 40-16-14-4,40-16-14-5, 40-16-14-5A, 40-16-14-6, 40-16-14-7, 40-16-14-8,40-16-14-8A, 40-16-14-9, 40-16-14-10, 40-16-14-10A, 40-16-14-11,40-16-14-12 and 40-16-14-13, which are group 16 compounds in groups16-14-1 through 16-14-13, (6) groups 40-17-14-1, 40-17-14-2, 40-17-14-3,40-17-14-4, 40-17-14-5, 40-17-14-5A, 40-17-14-6, 40-17-14-7, 40-17-14-8,40-17-14-8A, 40-17-14-9, 40-17-14-10, 40-17-14-10A, 40-17-14-11,40-17-14-12, 40-17-14-13, which are group 17 compounds in groups 17-14-1through 17-14-13, (7) groups 40-16-15-1, 40-16-15-2, 40-16-15-3,40-16-15-4, 40-16-15-5, 40-16-15-5A, 40-16-15-6, 40-16-15-7, 40-16-15-8,40-16-15-8A, 40-16-15-9, 40-16-15-10, 40-16-15-10A, 40-16-15-11,40-16-15-12, 40-16-15-13, which are group 16 compounds in groups 16-15-1through 16-15-13, (8) groups 40-17-15-1, 40-17-15-2, 40-17-15-3,40-17-15-4, 40-17-15-5, 40-17-15-5A, 40-17-15-6, 40-17-15-7, 40-17-15-8,40-17-15-8A, 40-17-15-9, 40-17-15-10, 40-17-15-10A, 40-17-15-11,40-17-15-12, 40-17-15-13, which are group 17 compounds in groups 17-15-1through 17-15-13, (9) groups 40-17-16-1, 40-17-16-2, 40-17-16-3,40-17-16-4, 40-17-16-5, 40-17-16-5A, 40-17-16-6, 40-17-16-7, 40-17-16-8,40-17-16-8A, 40-17-16-9, 40-17-16-10, 40-17-16-10A, 40-17-16-11,40-17-16-12, 40-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13, (10) groups 40-16-15-14-1, 40-16-15-14-2,40-16-15-14-3, 40-16-15-14-4, 40-16-15-14-5, 40-16-15-14-5A,40-16-15-14-6, 40-16-15-14-7, 40-16-15-14-8, 40-16-15-14-8A,40-16-15-14-9, 40-16-15-14-10, 40-16-15-14-10A, 40-16-15-14-11,40-16-15-14-12, 40-16-15-14-13, which are group 16 compounds in groups16-15-14-1 through 16-15-14-13, (11) groups 40-17-15-14-1,40-17-15-14-2, 40-17-15-14-3, 40-17-15-14-4, 40-17-15-14-5,40-17-15-14-5A, 40-17-15-14-6, 40-17-15-14-7, 40-17-15-14-8,40-17-15-14-8A, 40-17-15-14-9, 40-17-15-14-10, 40-17-15-14-10A,40-17-15-14-11, 40-17-15-14-12, 40-17-15-14-13, which are group 17compounds in groups 17-15-14-1 through 17-15-14-13, (12) groups40-17-16-14-1, 40-17-16-14-2, 40-17-16-14-3, 40-17-16-14-4,40-17-16-14-5, 40-17-16-14-5A, 40-17-16-14-6, 40-17-16-14-7,40-17-16-14-8, 40-17-16-14-8A, 40-17-16-14-9, 40-17-16-14-10,40-17-16-14-10A, 40-17-16-14-11, 40-17-16-14-12, 40-17-16-14-13, whichare group 17 compounds in groups 17-16-14-1 through 17-15-14-13, (13)groups 40-17-16-15-1, 40-17-16-15-2, 40-17-16-15-3, 40-17-16-15-4,40-17-16-15-5, 40-17-16-15-5A, 40-17-16-15-6, 40-17-16-15-7,40-17-16-15-8, 40-17-16-15-8A, 40-17-16-15-9, 40-17-16-15-10,40-17-16-15-10A, 40-17-16-15-11, 40-17-16-15-12 and 40-17-16-15-13,which are group 17 compounds in groups 17-16-15-1 through 17-16-15-13,(14) groups 40-17-16-15-14-1, 40-17-16-15-14-2, 40-17-16-15-14-3,40-17-16-15-14-4, 40-17-16-15-14-5, 40-17-16-15-14-5A, 40-17-16-15-14-6,40-17-16-15-14-7, 40-17-16-15-14-8, 40-17-16-15-14-8A, 40-17-16-15-14-9,40-17-16-15-14-10, 40-17-16-15-14-10A, 40-17-16-15-14-11,40-17-16-15-14-12 and 40-17-16-15-14-13, which are group 17 compounds ingroups 17-16-15-14-1 through 17-16-15-14-13, (15) all of the compoundsand/or groups described in group 18, (16) all of the compounds and/orgroups described in group 19, (17) all of the compounds and/or groupsdescribed in group 20, (18) all of the compounds and/or groups describedin groups 21, 22, 23, 24, 25, 26, 26A, 26B, 26C, 26E and 27, (19) all ofthe compounds and/or groups described in groups 28, 29, 30, 31, 32, 33,33A, 33B, 33C, 33D, 33E and 34 and (20) all of the compounds and/orgroups described in groups 35, 36, 37, 38, 39, 40, 40A, 40B, 40C, 40D,40E and 41.

Group 40A. This group contains compounds in groups 1-34 above where R³substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —N-pyrrolidine, 2 —N1-pyrazolone, 3 —N2-pyrazolone, 4—N-imidazolidin-2-one, 5 —N1-imidazole, 6 —N1-4,5-dihydroimidazole, 7—N-morpholine, 8 —N1-pyridine, 9 —N-piperidine, 10 —N-piperazine. Thecompounds in this group are described as in other groups describedabove, e.g., group 40A-3 compound 1.1.1.9 (i.e., group 40A compound1.1.1.9 from group 3) is 16α-N-pyrrolidinyl-3β,17β-dihydroxyandrost-5-ene.

These compounds include compounds in group 40A-1 through40A-41-34-27-20-19-18-17-16-15-14-13, which collectively are group 40Acompounds. These include groups 40A-1, 40A-2, 40A-3, 40A-4, 40A-5,40A-5A, 40A-6, 40A-7, 40A-8, 40A-8A, 40A-9, 40A-10, 40A-10A, 40A-11,40A-12, 40A-13, which are compounds in groups 1 through 13 where R³substituents 1-10 in Table A are replaced with the moieties given inthis group. Group 40A compounds also include groups 40A-14-1, 40A-14-2,40A-14-3, 40A-14-4, 40A-14-5, 40A-14-5A, 40A-14-6, 40A-14-7, 40A-14-8,40A-14-8A, 40A-14-9, 40A-14-10, 40A-14-10A, 40A-14-11, 40A-14-12 and40A-14-13, which are group 14 compounds in groups 14-1 through 14-13where R³ substituents 1-10 in Table A are replaced with the moietiesgiven in this group.

Other group 40A compounds include (1) groups 40A-15-1, 40A-15-2,40A-15-3, 40A-15-4, 40A-15-5, 40A-15-5A, 40A-15-6, 40A-15-7, 40A-15-8,40A-15-8A, 40A-15-9, 40A-15-10, 40A-15-10A, 40A-15-11, 40A-15-12 and40A-15-13, which are group 15 compounds in groups 15-1 through 15-13,(2) groups 40A-16-1, 40A-16-2, 40A-16-3, 40A-16-4, 40A-16-5, 40A-16-5A,40A-16-6, 40A-16-7, 40A-16-8, 40A-16-8A, 40A-16-9, 40A-16-10,40A-16-10A, 40A-16-11, 40A-16-12 and 40A-16-13, which are group 16compounds in groups 16-1 through 16-13, (3) groups 40A-17-1, 40A-17-2,40A-17-3, 40A-17-4, 40A-17-5, 40A-17-5A, 40A-17-6, 40A-17-7, 40A-17-8,40A-17-8A, 40A-17-9, 40A-17-10, 40A-17-10A, 40A-17-11, 40A-17-12 and40A-17-13, which are group 17 compounds in groups 17-1 through 17-13,(4) groups 40A-15-14-1, 40A-15-14-2, 40A-15-14-3, 40A-15-14-4,40A-15-14-5, 40A-15-14-5A, 40A-15-14-6, 40A-15-14-7, 40A-15-14-8,40A-15-14-8A, 40A-15-14-9, 40A-15-14-10, 40A-15-14-10A, 40A-15-14-11,40A-15-14-12 and 40A-15-14-13, which are group 15 compounds in groups15-14-1 through 15-14-13, (5) groups 40A-16-14-1, 40A-16-14-2,40A-16-14-3, 40A-16-14-4, 40A-16-14-5, 40A-16-14-5A, 40A-16-14-6,40A-16-14-7, 40A-16-14-8, 40A-16-14-8A, 40A-16-14-9, 40A-16-14-10,40A-16-14-10A, 40A-16-14-11, 40A-16-14-12 and 40A-16-14-13, which aregroup 16 compounds in groups 16-14-1 through 16-14-13, (6) groups40A-17-14-1, 40A-17-14-2, 40A-17-14-3, 40A-17-14-4, 40A-17-14-5,40A-17-14-5A, 40A-17-14-6, 40A-17-14-7, 40A-17-14-8, 40A-17-14-8A,40A-17-14-9, 40A-17-14-10, 40A-17-14-10A, 40A-17-14-11, 40A-17-14-12,40A-17-14-13, which are group 17 compounds in groups 17-14-1 through17-14-13, (7) groups 40A-16-15-1, 40A-16-15-2, 40A-16-15-3, 40A-16-15-4,40A-16-15-5, 40A-16-15-5A, 40A-16-15-6, 40A-16-15-7, 40A-16-15-8,40A-16-15-8A, 40A-16-15-9, 40A-16-15-10, 40A-16-15-10A, 40A-16-15-11,40A-16-15-12, 40A-16-15-13, which are group 16 compounds in groups16-15-1 through 16-15-13, (8) groups 40A-17-15-1, 40A-17-15-2,40A-17-15-3, 40A-17-15-4, 40A-17-15-5, 40A-17-15-5A, 40A-17-15-6,40A-17-15-7, 40A-17-15-8, 40A-17-15-8A, 40A-17-15-9, 40A-17-15-10,40A-17-15-10A, 40A-17-15-11, 40A-17-15-12, 40A-17-15-13, which are group17 compounds in groups 17-15-1 through 17-15-13, (9) groups 40A-17-16-1,40A-17-16-2, 40A-17-16-3, 40A-17-16-4, 40A-17-16-5, 40A-17-16-5A,40A-17-16-6, 40A-17-16-7, 40A-17-16-8, 40A-17-16-8A, 40A-17-16-9,40A-17-16-10, 40A-17-16-10A, 40A-17-16-11, 40A-17-16-12, 40A-17-16-13,which are group 17 compounds in groups 17-16-1 through 17-16-13, (10)groups 40A-16-15-14-1, 40A-16-15-14-2, 40A-16-15-14-3, 40A-16-15-14-4,40A-16-15-14-5, 40A-16-15-14-5A, 40A-16-15-14-6, 40A-16-15-14-7,40A-16-15-14-8, 40A-16-15-14-8A, 40A-16-15-14-9, 40A-16-15-14-10,40A-16-15-14-10A, 40A-16-15-14-11, 40A-16-15-14-12, 40A-16-15-14-13,which are group 16 compounds in groups 16-15-14-1 through 16-15-14-13,(11) groups 40A-17-15-14-1, 40A-17-15-14-2, 40A-17-15-14-3,40A-17-15-14-4, 40A-17-15-14-5, 40A-17-15-14-5A, 40A-17-15-14-6,40A-17-15-14-7, 40A-17-15-14-8, 40A-17-15-14-8A, 40A-17-15-14-9,40A-17-15-14-10, 40A-17-15-14-10A, 40A-17-15-14-11, 40A-17-15-14-12,40A-17-15-14-13, which are group 17 compounds in groups 17-15-14-1through 17-15-14-13, (12) groups 40A-17-16-14-1, 40A-17-16-14-2,40A-17-16-14-3, 40A-17-16-14-4, 40A-17-16-14-5, 40A-17-16-14-5A,40A-17-16-14-6, 40A-17-16-14-7, 40A-17-16-14-8, 40A-17-16-14-8A,40A-17-16-14-9, 40A-17-16-14-10, 40A-17-16-14-10A, 40A-17-16-14-11,40A-17-16-14-12, 40A-17-16-14-13, which are group 17 compounds in groups17-16-14-1 through 17-15-14-13, (13) groups 40A-17-16-15-1,40A-17-16-15-2, 40A-17-16-15-3, 40A-17-16-15-4, 40A-17-16-15-5,40A-17-16-15-5A, 40A-17-16-15-6, 40A-17-16-15-7, 40A-17-16-15-8,40A-17-16-15-8A, 40A-17-16-15-9, 40A-17-16-15-10, 40A-17-16-15-10A,40A-17-16-15-11, 40A-17-16-15-12 and 40A-17-16-15-13, which are group 17compounds in groups 17-16-15-1 through 17-16-15-13, (14) groups40A-17-16-15-14-1, 40A-17-16-15-14-2, 40A-17-16-15-14-3,40A-17-16-15-14-4, 40A-17-16-15-14-5, 40A-17-16-15-14-5A,40A-17-16-15-14-6, 40A-17-16-15-14-7, 40A-17-16-15-14-8,40A-17-16-15-14-8A, 40A-17-16-15-14-9, 40A-17-16-15-14-10,40A-17-16-15-14-10A, 40A-17-16-15-14-11, 40A-17-16-15-14-12 and40A-17-16-15-14-13, which are group 17 compounds in groups 17-16-15-14-1through 17-16-15-14-13, (15) all of the compounds and/or groupsdescribed in group 18, (16) all of the compounds and/or groups describedin group 19, (17) all of the compounds and/or groups described in group20, (18) all of the compounds and/or groups described in groups 21, 22,23, 24, 25, 26, 26A, 26B, 26C, 26E and 27, (19) all of the compoundsand/or groups described in groups 28, 29, 30, 31, 32, 33, 33A, 33B, 33C,33D, 33E and 34 and (20) all of the compounds and/or groups described ingroups 35, 36, 37, 38, 39, 40, 40A, 40B, 40C, 40D, 40E and 41.

Group 40B. This group contains compounds in groups 1-34 above where R³substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —N-piperazine substituted at N4 with optionally substitutedalkyl, 2 —N-indole, 3 —N-indoline, 4 —N-quinolidine, 5—NH—C(O)—CH₂—CH₂—C(O)—OH, 6 —NH—C(O)—CH₂—C(O)—OH, 7—NH—C(O)—CH₂—CH₂—C(O)—OR^(PR), 8 —NH—C(O)—CH₂—C(O)—OR^(PR), 9—NH—C(O)—(CH₂)₃—C(O)—OH, 10 —NH—C(O)—(CH₂)₃—C(O)—OR^(PR). Ionizablemoieties such as free carboxyl groups include salts, e.g., Na⁺ or K⁺.R^(PR) is a protecting group.

Group 40C. This group contains compounds in groups 1-34 above where R³substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —NH—CH(CH₃)—C(O)OH, 2 —NH—CH(CH₃)—C(O)OR^(PR), 3—NH—CH(CH₂OH)—C(O)OH, 4 —NH—CH(CH₂OH)—C(O)OR^(PR), 5—NH—CH₂—CH₂—C(O)—OH, 6 —NH—CH₂—C(O)—OH, 7 —NH—CH₂—CH₂—C(O)—OR^(PR), 8—NH—CH₂—C(O)—OR^(PR), 9 —NH—(CH₂)₃—C(O)—OH, 10 —NH—(CH₂)₃—C(O)—OR^(PR).Ionizable moieties such as free carboxyl groups include salts, e.g., Na⁺or K⁺. R^(PR) is a protecting group.

Group 40D. This group contains compounds in groups 1-34 above where R³substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —NH—CH(CH₃)—C(O)OH, 2 —NH—NH—C(O)CH₃, 3 —NH—NH—C(O)OCH₃, 4—NH—NH—C(O)C₂H₅, 5 —NH—NH—C(O)OC₂H₅, 6 —NH—NH—C(O)C₃H₇, 7—NH—NH—C(O)-optionally substituted alkyl, 8 —NH—C(NH-optionallysubstituted alkyl)=N-optionally substituted alkyl, 9—NH—C(NH—CH₃)═N—CH₃, 10 —NH—C(NH—C₂H₅)═N—C₂H₅.

Group 40E. This group contains compounds in groups 1-34 above where R³substituents 1-10 listed in Table A are replaced with the followinggroups: 1 spiro β-NH—(CH₂)₂—O-α, 2 spiro α-NH—(CH₂)₂—O-β, 3 spiroβ-NH—(CH₂)₂—NH-α, 4 spiro α-NH—(CH₂)₂—NH-β, 5 spiro β-NH—CH═N—CH₂-α, 6spiro α-NH—CH═N—CH₂-β, 7 spiro β-NH—CHR¹⁰—CHR¹⁰—O-α, 8 spiroα-NH—CHR¹⁰—CHR¹⁰—O-β, 9 spiro β-NH—CHR¹⁰—CHR¹⁰—NH-α, 10 spiroα-NH—CHR¹⁰—CHR¹⁰—NH—O—. Each R¹⁰ is independently chosen and has themeaning given above, e.g., —H, —OH, ═O, —SH, ═S, halogen or optionallysubstituted alkyl.

Group 41. This group contains compounds in groups 1-34 above where R³substituents 1-10 listed in Table A are replaced with the followinggroups: 1-glycol, e.g., propylene glycol or ethylene glycol,2-polyethylene glycol, e.g., PEG 100 or PEG 200, 3 -an acetal ring, 4-aspiro ring, 5-a thioacetal ring, 6 spiro —O—CH₂—O—, 7 spiro—O—(CH₂)₂—O—, 8 spiro —NH—(CH₂)₂—O—, 9 —NH—C(O)—(CH₂)₂—C(O)O—CH₃, 10—NH—C(O)—(CH₂)₂—C(O)—OH.

Group 42. This group contains compounds in groups 1-41 above where R²substituents 1-10 listed in Table A are replaced with the followinggroups: 1-optionally substituted amine, 2-optionally substituted amide,3-optionally substituted oxime, 4 -optionally substituted alkyl,5-optionally substituted alkenyl, 6-optionally substituted alkynyl,7-optionally substituted aryl, 8-optionally substituted heterocycle,9-ether and 10-ester. Any of these groups can be a moiety defined ordescribed herein for that moiety, e.g., optionally substituted amineincludes —NH₂, —NH₃ ⁺Cl⁻, —NH₃ ⁺Br⁻, —NH₃ ⁺I⁻, —NHCH₃, —N(CH₃)₂,—NHC₂H₅, —N(C₂H₅)₂, —NHC₃H₇, —N(C₃H₇)₂, —NHC₄H₉, —N(C₄H₉)₂,—NH-optionally substituted alkyl, —N(optionally substituted alkyl)₂,—NH—C₆H₅, —N(C₆H₅)₂, —NH-optionally substituted monosaccharide and—NH-optionally substituted oligosaccharide, and optionally substitutedamide includes —NHC(O)-optionally substituted alkyl,—N(CH₃)—C(O)-optionally substituted alkyl, —N(C₂H₅)—C(O)-optionallysubstituted alkyl, —N(C₃H₇)—C(O)-optionally substituted alkyl,—N(C₄H₉)—C(O)-optionally substituted alkyl, —N(C₆H₅)—C(O)-optionallysubstituted alkyl, —NH—C(O)-optionally substituted monosaccharide and—NH—C(O)-optionally substituted oligosaccharide, where alkyl or phenylgroups are the same or different and are optionally substituted asdescribed herein.

These compounds include compounds in group 42-1 through42-41-34-27-20-19-18-17-16-15-14-13, which collectively are group 42compounds. These include groups 42-1, 42-2, 42-3, 42-4, 42-5, 42-5A,42-6, 42-7, 42-8, 42-8A, 42-9, 42-10, 42-10A, 42-11, 42-12, 42-13, whichare compounds in groups 1 through 13 where R² substituents 1-10 in TableA are replaced with the moieties given in this group. Group 42 compoundsalso include groups 42-14-1, 42-14-2, 42-14-3, 42-14-4, 42-14-5,42-14-5A, 42-14-6, 42-14-7, 42-14-8, 42-14-8A, 42-14-9, 42-14-10,42-14-10A, 42-14-11, 42-14-12 and 42-14-13, which are group 14 compoundsin groups 14-1 through 14-13 where R² substituents 1-10 in Table A arereplaced with the moieties given in this group.

Other group 42 compounds include (1) groups 42-15-1, 42-15-2, 42-15-3,42-15-4, 42-15-5, 42-15-5A, 42-15-6, 42-15-7, 42-15-8, 42-15-8A,42-15-9, 42-15-10, 42-15-10A, 42-15-11, 42-15-12 and 42-15-13, which aregroup 15 compounds in groups 15-1 through 15-13, (2) groups 42-16-1,42-16-2, 42-16-3, 42-16-4, 42-16-5, 42-16-5A, 42-16-6, 42-16-7, 42-16-8,42-16-8A, 42-16-9, 42-16-10, 42-16-10A, 42-16-11, 42-16-12 and 42-16-13,which are group 16 compounds in groups 16-1 through 16-13, (3) groups42-17-1, 42-17-2, 42-17-3, 42-17-4, 42-17-5, 42-17-5A, 42-17-6, 42-17-7,42-17-8, 42-17-8A, 42-17-9, 42-17-10, 42-17-10A, 42-17-11, 42-17-12 and42-17-13, which are group 17 compounds in groups 17-1 through 17-13, (4)groups 42-15-14-1, 42-15-14-2, 42-15-14-3, 42-15-14-4, 42-15-14-5,42-15-14-5A, 42-15-14-6, 42-15-14-7, 42-15-14-8, 42-15-14-8A,42-15-14-9, 42-15-14-10, 42-15-14-10A, 42-15-14-11, 42-15-14-12 and42-15-14-13, which are group 15 compounds in groups 15-14-1 through15-14-13, (5) groups 42-16-14-1, 42-16-14-2, 42-16-14-3, 42-16-14-4,42-16-14-5, 42-16-14-5A, 42-16-14-6, 42-16-14-7, 42-16-14-8,42-16-14-8A, 42-16-14-9, 42-16-14-10, 42-16-14-10A, 42-16-14-11,42-16-14-12 and 42-16-14-13, which are group 16 compounds in groups16-14-1 through 16-14-13, (6) groups 42-17-14-1, 42-17-14-2, 42-17-14-3,42-17-14-4, 42-17-14-5, 42-17-14-5A, 42-17-14-6, 42-17-14-7, 42-17-14-8,42-17-14-8A, 42-17-14-9, 42-17-14-10, 42-17-14-10A, 42-17-14-11,42-17-14-12, 42-17-14-13, which are group 17 compounds in groups 17-14-1through 17-14-13, (7) groups 42-16-15-1, 42-16-15-2, 42-16-15-3,42-16-15-4, 42-16-15-5, 42-16-15-5A, 42-16-15-6, 42-16-15-7, 42-16-15-8,42-16-15-8A, 42-16-15-9, 42-16-15-10, 42-16-15-10A, 42-16-15-11,42-16-15-12, 42-16-15-13, which are group 16 compounds in groups 16-15-1through 16-15-13, (8) groups 42-17-15-1, 42-17-15-2, 42-17-15-3,42-17-15-4, 42-17-15-5, 42-17-15-5A, 42-17-15-6, 42-17-15-7, 42-17-15-8,42-17-15-8A, 42-17-15-9, 42-17-15-10, 42-17-15-10A, 42-17-15-11,42-17-15-12, 42-17-15-13, which are group 17 compounds in groups 17-15-1through 17-15-13, (9) groups 42-17-16-1, 42-17-16-2, 42-17-16-3,42-17-16-4, 42-17-16-5, 42-17-16-5A, 42-17-16-6, 42-17-16-7, 42-17-16-8,42-17-16-8A, 42-17-16-9, 42-17-16-10, 42-17-16-10A, 42-17-16-11,42-17-16-12, 42-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13, (10) groups 42-16-15-14-1, 42-16-15-14-2,42-16-15-14-3, 42-16-15-14-4, 42-16-15-14-5, 42-16-15-14-5A,42-16-15-14-6, 42-16-15-14-7, 42-16-15-14-8, 42-16-15-14-8A,42-16-15-14-9, 42-16-15-14-10, 42-16-15-14-10A, 42-16-15-14-11,42-16-15-14-12, 42-16-15-14-13, which are group 16 compounds in groups16-15-14-1 through 16-15-14-13, (11) groups 42-17-15-14-1,42-17-15-14-2, 42-17-15-14-3, 42-17-15-14-4, 42-17-15-14-5,42-17-15-14-5A, 42-17-15-14-6, 42-17-15-14-7, 42-17-15-14-8,42-17-15-14-8A, 42-17-15-14-9, 42-17-15-14-10, 42-17-15-14-10A,42-17-15-14-11, 42-17-15-14-12, 42-17-15-14-13, which are group 17compounds in groups 17-15-14-1 through 17-15-14-13, (12) groups42-17-16-14-1, 42-17-16-14-2, 42-17-16-14-3, 42-17-16-14-4,42-17-16-14-5, 42-17-16-14-5A, 42-17-16-14-6, 42-17-16-14-7,42-17-16-14-8, 42-17-16-14-8A, 42-17-16-14-9, 42-17-16-14-10,42-17-16-14-10A, 42-17-16-14-11, 42-17-16-14-12, 42-17-16-14-13, whichare group 17 compounds in groups 17-16-14-1 through 17-15-14-13, (13)groups 42-17-16-15-1, 42-17-16-15-2, 42-17-16-15-3, 42-17-16-15-4,42-17-16-15-5, 42-17-16-15-5A, 42-17-16-15-6, 42-17-16-15-7,42-17-16-15-8, 42-17-16-15-8A, 42-17-16-15-9, 42-17-16-15-10,42-17-16-15-10A, 42-17-16-15-11, 42-17-16-15-12 and 42-17-16-15-13,which are group 17 compounds in groups 17-16-15-1 through 17-16-15-13,(14) groups 42-17-16-15-14-1, 42-17-16-15-14-2, 42-17-16-15-14-3,42-17-16-15-14-4, 42-17-16-15-14-5, 42-17-16-15-14-5A, 42-17-16-15-14-6,42-17-16-15-14-7, 42-17-16-15-14-8, 42-17-16-15-14-8A, 42-17-16-15-14-9,42-17-16-15-14-10, 42-17-16-15-14-10A, 42-17-16-15-14-11,42-17-16-15-14-12 and 42-17-16-15-14-13, which are group 17 compounds ingroups 17-16-15-14-1 through 17-16-15-14-13, (15) all of the compoundsand/or groups described in group 18, (16) all of the compounds and/orgroups described in group 19, (17) all of the compounds and/or groupsdescribed in group 20, (18) all of the compounds and/or groups describedin groups 21, 22, 23, 24, 25, 26, 26A, 26B, 26C, 26E and 27, (19) all ofthe compounds and/or groups described in groups 28, 29, 30, 31, 32, 33,33A, 33B, 33C, 33D, 33E and 34 and (20) all of the compounds and/orgroups described in groups 35, 36, 37, 38, 39, 40, 40A, 40B, 40C, 40D,40E and 41.

Group 43. This group contains compounds in groups 1-41 above where R²substituents 1-10 listed in Table A are replaced with the followinggroups: 1-acyl, 2 -thioester, 3-thioether, 4-thioacyl, 5-epoxide,6-optionally substituted cyclopropyl, 7 —O—Si(C1-C6 alkyl)₃,8-phosphate, 9-phosphate ester and 10-phosphate ether. Any of thesegroups can be a moiety defined herein for that group. The epoxide andoptionally substituted cyclopropyl moieties for substituents 5 and 6respectively can be at the 6-7 positions or at the 7-8 positions in theα- or β-configuration.

Group 44. This group contains compounds in groups 1-41 above where R²substituents 1-10 listed in Table A are replaced with the followinggroups: 1-phosphate thioether, 2-thionoester, 3-amino acid, 4-peptide,5-dipeptide, 6-optionally substituted heterocycle, 7-optionallysubstituted carboxyl, 8-carbonate, 9-carbamate and 10-phosphothioester.

Group 45. This group contains compounds in groups 1-41 above where R²substituents 1-10 listed in Table A are replaced with the followinggroups: 1 -thiophosphate, 2-phosphothioether, 3-thiophosphate thioether,4-phosphonoester, 5 -phosphonate, 6-phosphonate ester, 7-phosphonateether, 8-phosphonate thioether, 9 —O—S(O)(O)—OH and 10-sulfate salt,e.g., —O—S(O)(O)—O⁺Na⁻.

Group 46. This group contains compounds in groups 1-41 above where R²substituents 1-10 listed in Table A are replaced with the followinggroups: 1-sulfate ester, 2-sulfate ether, 3-sulfate thioether, 4—O—S(O)—OH, 5-sulfite salt, e.g., —O—S(O)—O⁺Na⁻, 6 -sulfite ester,7-sulfite ether, 8-sulfoxide, 9 —O—S(O)(O)—OR^(PR), and 10—O—S(O)(O)—OCH₃.

Group 47. This group contains compounds in groups 1-41 above where R²substituents 1-10 listed in Table A are replaced with the followinggroups: 1-sulfonamide, 2-sulfonamide derivative, e.g., —S(O)(O)—NHR^(PR)or —S(O)(O)—NH-optionally substituted alkyl, 3-sulfamate, 4-sulfamatederivative, e.g., —O—S(O)(O)—NHR^(PR), —O—S(O)(O)—NHCH₃,—O—S(O)(O)—NHC₂H₅, —O—S(O)(O)—NHC₃H₇, —O—S(O)(O)—NHC₄H₉,—O—S(O)(O)—N(RD)₂ or —O—S(O)(O)—NH-optionally substituted alkyl,5-sulfonate, 6-sulfamide, 7-sulfinamide, 8 -sulfurous diamide,9-optionally protected monosaccharide, e.g., D-, L- or DL-glucose,fructose, rhamnose or glucuronic acid, 10-optionally protectedoligosaccharide, e.g., D-, L- or DL-galactose-galactose,-galactose-mannose or -glucuronic acid-glucose. In this group, theoptionally protected monosaccharide and optionally protectedoligomonosaccharide moieties are typically linked to the 3-positionthrough an oxygen, sulfur or nitrogen atom.

Exemplary group 47 compounds include glycosides such as 7β-glycosidesand 7α-glycosides, 3β,17α-dihydroxyandrost-5-ene-7β-O-1′-β′-glucopyranose, 3α,17α-dihydroxyandrost-5-ene-7β-O-1′-β′-glucopyranose,3β-hydroxy-16α-fluoro-17-oxoandrost-5-ene-7β-O-1′-β′-glucopyranose, 3β,17β-dihydroxyandrost-5-ene-7α-1′-β′-glucopyranose, 3α,17β-dihydroxyandrost-5-ene-7β-O-1′-β′-glucopyranose,3α-hydroxy-16β-fluoro-17-oxoandrost-5-ene-7α-1′-β′-glucopyranose andanalogs of any of these compounds having one, two or more moietiesdescribed herein for variable groups, e.g., 16α-halo, 16β-halo, 4α-halo,4β-halo, 4α-alkyl, 4β-alkyl, 12α-halo, 12β-halo, 12α-alkyl, 12β-alkyl,11-dihalo, 11-alkyl, 11α-alkyl, 11-dialkyl, 12-dialkyl,12α-hydroxyorthiol, 12β-hydroxy or thiol, 12-oxo, 12α-halo, 12β-halo,12α-fluoro, 12β-fluoro, 12α-alkoxy, 12β-alkoxy, 2-oxa, 11-oxa, 15-oxa,19-nor (i.e., R⁶ is —H), 18-homo (i.e., R⁵ is —C₂H₅) or the like whereany alkyl or alkoxy moieties are optionally substituted. Other exemplarymoieties at R² include β-D-glucopyranosyl, β-D-glucopyranuronosyl,β-D-2-acetamido-2-deoxy-glucopyranosyl, β-D-galactopyranosyl,β-D-fucopyranosyl, β-L-fucopyranosyl, α-D-fructofuranosyl,β-D-fructofuranosyl, β-D-xylopyranosyl, β-L-xylopyranosyl,α-D-arabanopyranosyl, α-L-arabanopyranosyl, α-L-rhamnopyranosyl,α-D-rhamnopyranosyl, α-D-cellobiosyl, β-D-cellobiosyl, β-D-lactosyl,β-D-maltosyl, β-D-gentiobiosyl,3-O-β-D-galactopyranosyl-α-D-arabanopyranosyl or β-D-maltotriosyl, anyof which are optionally protected and where R² is in the α- orβ-configuration.

These compounds include compounds in group 47-1 through47-41-34-27-20-19-18-17-16-15-14-13, which collectively are group 47compounds. These include groups 47-1, 47-2, 47-3, 47-4, 47-5, 47-5A,47-6, 47-7, 47-8, 47-8A, 47-9, 47-10, 47-10A, 47-11, 47-12, 47-13, whichare compounds in groups 1 through 13 where R² substituents 1-10 in TableA are replaced with the moieties given in this group. Group 47 compoundsalso include groups 47-14-1, 47-14-2, 47-14-3, 47-14-4, 47-14-5,47-14-5A, 47-14-6, 47-14-7, 47-14-8, 47-14-8A, 47-14-9, 47-14-10,47-14-10A, 47-14-11, 47-14-12 and 47-14-13, which are group 14 compoundsin groups 14-1 through 14-13 where R² substituents 1-10 in Table A arereplaced with the moieties given in this group.

Other group 47 compounds include (1) groups 47-15-1, 47-15-2, 47-15-3,47-15-4, 47-15-5, 47-15-5A, 47-15-6, 47-15-7, 47-15-8, 47-15-8A,47-15-9, 47-15-10, 47-15-10A, 47-15-11, 47-15-12 and 47-15-13, which aregroup 15 compounds in groups 15-1 through 15-13, (2) groups 47-16-1,47-16-2, 47-16-3, 47-16-4, 47-16-5, 47-16-5A, 47-16-6, 47-16-7, 47-16-8,47-16-8A, 47-16-9, 47-16-10, 47-16-10A, 47-16-11, 47-16-12 and 47-16-13,which are group 16 compounds in groups 16-1 through 16-13, (3) groups47-17-1, 47-17-2, 47-17-3, 47-17-4, 47-17-5, 47-17-5A, 47-17-6, 47-17-7,47-17-8, 47-17-8A, 47-17-9, 47-17-10, 47-17-10A, 47-17-11, 47-17-12 and47-17-13, which are group 17 compounds in groups 17-1 through 17-13, (4)groups 47-15-14-1, 47-15-14-2, 47-15-14-3, 47-15-14-4, 47-15-14-5,47-15-14-5A, 47-15-14-6, 47-15-14-7, 47-15-14-8, 47-15-14-8A,47-15-14-9, 47-15-14-10, 47-15-14-10A, 47-15-14-11, 47-15-14-12 and47-15-14-13, which are group 15 compounds in groups 15-14-1 through15-14-13, (5) groups 47-16-14-1, 47-16-14-2, 47-16-14-3, 47-16-14-4,47-16-14-5, 47-16-14-5A, 47-16-14-6, 47-16-14-7, 47-16-14-8,47-16-14-8A, 47-16-14-9, 47-16-14-10, 47-16-14-10A, 47-16-14-11,47-16-14-12 and 47-16-14-13, which are group 16 compounds in groups16-14-1 through 16-14-13, (6) groups 47-17-14-1, 47-17-14-2, 47-17-14-3,47-17-14-4, 47-17-14-5, 47-17-14-5A, 47-17-14-6, 47-17-14-7, 47-17-14-8,47-17-14-8A, 47-17-14-9, 47-17-14-10, 47-17-14-10A, 47-17-14-11,47-17-14-12, 47-17-14-13, which are group 17 compounds in groups 17-14-1through 17-14-13, (7) groups 47-16-15-1, 47-16-15-2, 47-16-15-3,47-16-15-4, 47-16-15-5, 47-16-15-5A, 47-16-15-6, 47-16-15-7, 47-16-15-8,47-16-15-8A, 47-16-15-9, 47-16-15-10, 47-16-15-10A, 47-16-15-11,47-16-15-12, 47-16-15-13, which are group 16 compounds in groups 16-15-1through 16-15-13, (8) groups 47-17-15-1, 47-17-15-2, 47-17-15-3,47-17-15-4, 47-17-15-5, 47-17-15-5A, 47-17-15-6, 47-17-15-7, 47-17-15-8,47-17-15-8A, 47-17-15-9, 47-17-15-10, 47-17-15-10A, 47-17-15-11,47-17-15-12, 47-17-15-13, which are group 17 compounds in groups 17-15-1through 17-15-13, (9) groups 47-17-16-1, 47-17-16-2, 47-17-16-3,47-17-16-4, 47-17-16-5, 47-17-16-5A, 47-17-16-6, 47-17-16-7, 47-17-16-8,47-17-16-8A, 47-17-16-9, 47-17-16-10, 47-17-16-10A, 47-17-16-11,47-17-16-12, 47-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13, (10) groups 47-16-15-14-1, 47-16-15-14-2,47-16-15-14-3, 47-16-15-14-4, 47-16-15-14-5, 47-16-15-14-5A,47-16-15-14-6, 47-16-15-14-7, 47-16-15-14-8, 47-16-15-14-8A,47-16-15-14-9, 47-16-15-14-10, 47-16-15-14-10A, 47-16-15-14-11,47-16-15-14-12, 47-16-15-14-13, which are group 16 compounds in groups16-15-14-1 through 16-15-14-13, (11) groups 47-17-15-14-1,47-17-15-14-2, 47-17-15-14-3, 47-17-15-14-4, 47-17-15-14-5,47-17-15-14-5A, 47-17-15-14-6, 47-17-15-14-7, 47-17-15-14-8,47-17-15-14-8A, 47-17-15-14-9, 47-17-15-14-10, 47-17-15-14-10A,47-17-15-14-11, 47-17-15-14-12, 47-17-15-14-13, which are group 17compounds in groups 17-15-14-1 through 17-15-14-13, (12) groups47-17-16-14-1, 47-17-16-14-2, 47-17-16-14-3, 47-17-16-14-4,47-17-16-14-5, 47-17-16-14-5A, 47-17-16-14-6, 47-17-16-14-7,47-17-16-14-8, 47-17-16-14-8A, 47-17-16-14-9, 47-17-16-14-10,47-17-16-14-10A, 47-17-16-14-11, 47-17-16-14-12, 47-17-16-14-13, whichare group 17 compounds in groups 17-16-14-1 through 17-15-14-13, (13)groups 47-17-16-15-1, 47-17-16-15-2, 47-17-16-15-3, 47-17-16-15-4,47-17-16-15-5, 47-17-16-15-5A, 47-17-16-15-6, 47-17-16-15-7,47-17-16-15-8, 47-17-16-15-8A, 47-17-16-15-9, 47-17-16-15-10,47-17-16-15-10A, 47-17-16-15-11, 47-17-16-15-12 and 47-17-16-15-13,which are group 17 compounds in groups 17-16-15-1 through 17-16-15-13,(14) groups 47-17-16-15-14-1, 47-17-16-15-14-2, 47-17-16-15-14-3,47-17-16-15-14-4, 47-17-16-15-14-5, 47-17-16-15-14-5A, 47-17-16-15-14-6,47-17-16-15-14-7, 47-17-16-15-14-8, 47-17-16-15-14-8A, 47-17-16-15-14-9,47-17-16-15-14-10, 47-17-16-15-14-10A, 47-17-16-15-14-11,47-17-16-15-14-12 and 47-17-16-15-14-13, which are group 17 compounds ingroups 17-16-15-14-1 through 17-16-15-14-13, (15) all of the compoundsand/or groups described in group 18, (16) all of the compounds and/orgroups described in group 19, (17) all of the compounds and/or groupsdescribed in group 20, (18) all of the compounds and/or groups describedin groups 21, 22, 23, 24, 25, 26, 26A, 26B, 26C, 26E and 27, (19) all ofthe compounds and/or groups described in groups 28, 29, 30, 31, 32, 33,33A, 33B, 33C, 33D, 33E and 34 and (20) all of the compounds and/orgroups described in groups 35, 36, 37, 38, 39, 40, 40A, 40B, 40C, 40D,40E and 41.

Group 47A. This group contains compounds in groups 1-41 above where R²substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —N-pyrrolidine, 2 —N1-pyrazolone, 3 —N2-pyrazolone, 4—N-imidazolidin-2-one, 5 —N1-imidazole, 6 —N1-4,5-dihydroimidazole, 7—N-morpholine, 8 —N1-pyridine, 9 —N-piperidine, 10 —N-piperazine.

These compounds include compounds in group 47A-1 through47A-41-34-27-20-19-18-17-16-15-14-13, which collectively are group 47Acompounds. These include groups 47A-1, 47A-2, 47A-3, 47A-4, 47A-5,47A-5A, 47A-6, 47A-7, 47A-8, 47A-8A, 47A-9, 47A-10, 47A-10A, 47A-11,47A-12, 47A-13, which are compounds in groups 1 through 13 where R²substituents 1-10 in Table A are replaced with the moieties given inthis group. Group 47A compounds also include groups 47A-14-1, 47A-14-2,47A-14-3, 47A-14-4, 47A-14-5, 47A-14-5A, 47A-14-6, 47A-14-7, 47A-14-8,47A-14-8A, 47A-14-9, 47A-14-10, 47A-14-10A, 47A-14-11, 47A-14-12 and47A-14-13, which are group 14 compounds in groups 14-1 through 14-13where R² substituents 1-10 in Table A are replaced with the moietiesgiven in this group.

Other group 47A compounds include (1) groups 47A-15-1, 47A-15-2,47A-15-3, 47A-15-4, 47A-15-5, 47A-15-5A, 47A-15-6, 47A-15-7, 47A-15-8,47A-15-8A, 47A-15-9, 47A-15-10, 47A-15-10A, 47A-15-11, 47A-15-12 and47A-15-13, which are group 15 compounds in groups 15-1 through 15-13,(2) groups 47A-16-1, 47A-16-2, 47A-16-3, 47A-16-4, 47A-16-5, 47A-16-5A,47A-16-6, 47A-16-7, 47A-16-8, 47A-16-8A, 47A-16-9, 47A-16-10,47A-16-10A, 47A-16-11, 47A-16-12 and 47A-16-13, which are group 16compounds in groups 16-1 through 16-13, (3) groups 47A-17-1, 47A-17-2,47A-17-3, 47A-17-4, 47A-17-5, 47A-17-5A, 47A-17-6, 47A-17-7, 47A-17-8,47A-17-8A, 47A-17-9, 47A-17-10, 47A-17-10A, 47A-17-11, 47A-17-12 and47A-17-13, which are group 17 compounds in groups 17-1 through 17-13,(4) groups 47A-15-14-1, 47A-15-14-2, 47A-15-14-3, 47A-15-14-4,47A-15-14-5, 47A-15-14-5A, 47A-15-14-6, 47A-15-14-7, 47A-15-14-8,47A-15-14-8A, 47A-15-14-9, 47A-15-14-10, 47A-15-14-10A, 47A-15-14-11,47A-15-14-12 and 47A-15-14-13, which are group 15 compounds in groups15-14-1 through 15-14-13, (5) groups 47A-16-14-1, 47A-16-14-2,47A-16-14-3, 47A-16-14-4, 47A-16-14-5, 47A-16-14-5A, 47A-16-14-6,47A-16-14-7, 47A-16-14-8, 47A-16-14-8A, 47A-16-14-9, 47A-16-14-10,47A-16-14-10A, 47A-16-14-11, 47A-16-14-12 and 47A-16-14-13, which aregroup 16 compounds in groups 16-14-1 through 16-14-13, (6) groups47A-17-14-1, 47A-17-14-2, 47A-17-14-3, 47A-17-14-4, 47A-17-14-5,47A-17-14-5A, 47A-17-14-6, 47A-17-14-7, 47A-17-14-8, 47A-17-14-8A,47A-17-14-9, 47A-17-14-10, 47A-17-14-10A, 47A-17-14-11, 47A-17-14-12,47A-17-14-13, which are group 17 compounds in groups 17-14-1 through17-14-13, (7) groups 47A-16-15-1, 47A-16-15-2, 47A-16-15-3, 47A-16-15-4,47A-16-15-5, 47A-16-15-5A, 47A-16-15-6, 47A-16-15-7, 47A-16-15-8,47A-16-15-8A, 47A-16-15-9, 47A-16-15-10, 47A-16-15-10A, 47A-16-15-11,47A-16-15-12, 47A-16-15-13, which are group 16 compounds in groups16-15-1 through 16-15-13, (8) groups 47A-17-15-1, 47A-17-15-2,47A-17-15-3, 47A-17-15-4, 47A-17-15-5, 47A-17-15-5A, 47A-17-15-6,47A-17-15-7, 47A-17-15-8, 47A-17-15-8A, 47A-17-15-9, 47A-17-15-10,47A-17-15-10A, 47A-17-15-11, 47A-17-15-12, 47A-17-15-13, which are group17 compounds in groups 17-15-1 through 17-15-13, (9) groups 47A-17-16-1,47A-17-16-2, 47A-17-16-3, 47A-17-16-4, 47A-17-16-5, 47A-17-16-5A,47A-17-16-6, 47A-17-16-7, 47A-17-16-8, 47A-17-16-8A, 47A-17-16-9,47A-17-16-10, 47A-17-16-10A, 47A-17-16-11, 47A-17-16-12, 47A-17-16-13,which are group 17 compounds in groups 17-16-1 through 17-16-13, (10)groups 47A-16-15-14-1, 47A-16-15-14-2, 47A-16-15-14-3, 47A-16-15-14-4,47A-16-15-14-5, 47A-16-15-14-5A, 47A-16-15-14-6, 47A-16-15-14-7,47A-16-15-14-8, 47A-16-15-14-8A, 47A-16-15-14-9, 47A-16-15-14-10,47A-16-15-14-10A, 47A-16-15-14-11, 47A-16-15-14-12, 47A-16-15-14-13,which are group 16 compounds in groups 16-15-14-1 through 16-15-14-13,(11) groups 47A-17-15-14-1, 47A-17-15-14-2, 47A-17-15-14-3,47A-17-15-14-4, 47A-17-15-14-5, 47A-17-15-14-5A, 47A-17-15-14-6,47A-17-15-14-7, 47A-17-15-14-8, 47A-17-15-14-8A, 47A-17-15-14-9,47A-17-15-14-10, 47A-17-15-14-10A, 47A-17-15-14-11, 47A-17-15-14-12,47A-17-15-14-13, which are group 17 compounds in groups 17-15-14-1through 17-15-14-13, (12) groups 47A-17-16-14-1, 47A-17-16-14-2,47A-17-16-14-3, 47A-17-16-14-4, 47A-17-16-14-5, 47A-17-16-14-5A,47A-17-16-14-6, 47A-17-16-14-7, 47A-17-16-14-8, 47A-17-16-14-8A,47A-17-16-14-9, 47A-17-16-14-10, 47A-17-16-14-10A, 47A-17-16-14-11,47A-17-16-14-12, 47A-17-16-14-13, which are group 17 compounds in groups17-16-14-1 through 17-15-14-13, (13) groups 47A-17-16-15-1,47A-17-16-15-2, 47A-17-16-15-3, 47A-17-16-15-4, 47A-17-16-15-5,47A-17-16-15-5A, 47A-17-16-15-6, 47A-17-16-15-7, 47A-17-16-15-8,47A-17-16-15-8A, 47A-17-16-15-9, 47A-17-16-15-10, 47A-17-16-15-10A,47A-17-16-15-11, 47A-17-16-15-12 and 47A-17-16-15-13, which are group 17compounds in groups 17-16-15-1 through 17-16-15-13, (14) groups47A-17-16-15-14-1, 47A-17-16-15-14-2, 47A-17-16-15-14-3,47A-17-16-15-14-4, 47A-17-16-15-14-5, 47A-17-16-15-14-5A,47A-17-16-15-14-6, 47A-17-16-15-14-7, 47A-17-16-15-14-8,47A-17-16-15-14-8A, 47A-17-16-15-14-9, 47A-17-16-15-14-10,47A-17-16-15-14-10A, 47A-17-16-15-14-11, 47A-17-16-15-14-12 and47A-17-16-15-14-13, which are group 17 compounds in groups 17-16-15-14-1through 17-16-15-14-13, (15) all of the compounds and/or groupsdescribed in group 18, (16) all of the compounds and/or groups describedin group 19, (17) all of the compounds and/or groups described in group20, (18) all of the compounds and/or groups described in groups 21, 22,23, 24, 25, 26, 26A, 26B, 26C, 26E and 27, (19) all of the compoundsand/or groups described in groups 28, 29, 30, 31, 32, 33, 33A, 33B, 33C,33D, 33E and 34 and (20) all of the compounds and/or groups described ingroups 35, 36, 37, 38, 39, 40, 40A, 40B, 40C, 40D, 40E and 41.

Group 47B. This group contains compounds in groups 1-41 above where R²substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —N-piperazine substituted at N4 with optionally substitutedalkyl, 2 —N-indole, 3 —N-indoline, 4 —N-quinolidine, 5—NH—C(O)—CH₂—CH₂—C(O)—OH, 6 —NH—C(O)—CH₂—C(O)—OH, 7—NH—C(O)—CH₂—CH₂—C(O)—OR^(PR), 8 —NH—C(O)—CH₂—C(O)—OR^(PR), 9—NH—C(O)—(CH₂)₃—C(O)—OH, 10 —NH—C(O)—(CH₂)₃—C(O)—OR^(PR). Ionizablemoieties such as free carboxyl groups include salts, e.g., Na⁺ or K⁺.R^(PR) is a protecting group.

Group 47C. This group contains compounds in groups 1-41 above where R²substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —NH—CH(CH₃)—C(O)OH, 2 —NH—CH(CH₃)—C(O)OR^(PR), 3—NH—CH(CH₂OH)—C(O)OH, 4 —NH—CH(CH₂OH)—C(O)OR^(PR), 5—NH—CH₂—CH₂—C(O)—OH, 6 —NH—CH₂—C(O)—OH, 7 —NH—CH₂—CH₂—C(O)—OR^(PR), 8—NH—CH₂—C(O)—OR^(PR), 9 —NH—(CH₂)₃—C(O)—OH, 10 —NH—(CH₂)₃—C(O)—OR^(PR).Ionizable moieties such as free carboxyl groups include salts, e.g., Na⁺or K⁺. R^(PR) is a protecting group.

Group 47D. This group contains compounds in groups 1-41 above where R²substituents 1-10 listed in Table A are replaced with the followinggroups: 1 —NH—CH(CH₃)—C(O)OH, 2 —NH—NH—C(O)CH₃, 3 —NH—NH—C(O)OCH₃, 4—NH—NH—C(O)C₂H₅, 5 —NH—NH—C(O)OC₂H₅, 6 —NH—NH—C(O)C₃H₇, 7—NH—NH—C(O)-optionally substituted alkyl, 8 —NH—C(NH-optionallysubstituted alkyl)=N-optionally substituted alkyl, 9—NH—C(NH—CH₃)═N—CH₃, 10 —NH—C(NH—C₂H₅)═N—C₂H₅.

Group 47E. This group contains compounds in groups 1-41 above where R²substituents 1-10 listed in Table A are replaced with the followinggroups: 1 spiro β-NH—(CH₂)₂—O-α, 2 spiro α-NH—(CH₂)₂—O-β, 3 spiroβ-NH—(CH₂)₂—NH-α, 4 spiro α-NH—(CH₂)₂—NH-β, 5 spiro β-NH—CH═N—CH₂-α, 6spiro α-NH—CH═N—CH₂-β, 7 spiro β-NH—CHR¹⁰—CHR¹⁰—O-α, 8 spiroα-NH—CHR¹⁰—CHR¹⁰—O-β, 9 spiro β-NH—CHR¹⁰—CHR¹⁰—NH-α, 10 spiroα-NH—CHR¹⁰—CHR¹⁰—NH—O—. Each R¹⁰ is independently chosen and has themeaning given above, e.g., —H, —OH, ═O, —SH, ═S, halogen or optionallysubstituted alkyl.

Group 48. This group contains compounds in groups 1-41 above where R²substituents 1-10 listed in Table A are replaced with the followinggroups: 1-glycol, e.g., propylene glycol or ethylene glycol,2-polyethylene glycol, e.g., PEG 100 or PEG 200, 3 -an acetal ring, 4-aspiro ring, 5-a thioacetal ring, 6 spiro —O—CH₂—O—, 7 spiro—O—(CH₂)₂—O—, 8 spiro —NH—(CH₂)₂—O—, 9 —NH—C(O)—(CH₂)₂—C(O)O—CH₃, 10—NH—C(O)—(CH₂)₂—C(O)—OH.

Group 49. This group contains compounds in groups 1-48 above wherein R⁴is single bonded and a second R⁴ that is not —H is present. The secondR⁴ can be a moiety defined herein for R⁴, e.g., optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,halogen, ester, —OH, —CH₃, —C₂H₅, —C₃H₇, —CN, —C≡CH, —C≡C-halogen,—C≡C—OH, —C≡C—CH₃, —C═CH₂, —CH₂—C═CH₂, —NH₂, —SH or —OH.

These compounds include compounds in group 49-1 through49-48-41-34-27-20-19-18-17-16-15-14-13, which collectively are group 49compounds. These include groups 49-1, 49-2, 49-3, 49-4, 49-5, 49-5A,49-6, 49-7, 49-8, 49-8A, 49-9, 49-10, 49-10A, 49-11, 49-12, 49-13, whichare compounds in groups 1 through 13 where a second R⁴ substituent ispresent. Group 49 compounds also include groups 49-14-1, 49-14-2,49-14-3, 49-14-4, 49-14-5, 49-14-5A, 49-14-6, 49-14-7, 49-14-8,49-14-8A, 49-14-9, 49-14-10, 49-14-10A, 49-14-11, 49-14-12 and 49-14-13,which are group 14 compounds in groups 14-1 through 14-13 where a secondR⁴ substituent is present.

Other group 49 compounds include (1) groups 49-15-1, 49-15-2, 49-15-3,49-15-4, 49-15-5, 49-15-5A, 49-15-6, 49-15-7, 49-15-8, 49-15-8A,49-15-9, 49-15-10, 49-15-10A, 49-15-11, 49-15-12 and 49-15-13, which aregroup 15 compounds in groups 15-1 through 15-13, (2) groups 49-16-1,49-16-2, 49-16-3, 49-16-4, 49-16-5, 49-16-5A, 49-16-6, 49-16-7, 49-16-8,49-16-8A, 49-16-9, 49-16-10, 49-16-10A, 49-16-11, 49-16-12 and 49-16-13,which are group 16 compounds in groups 16-1 through 16-13, (3) groups49-17-1, 49-17-2, 49-17-3, 49-17-4, 49-17-5, 49-17-5A, 49-17-6, 49-17-7,49-17-8, 49-17-8A, 49-17-9, 49-17-10, 49-17-10A, 49-17-11, 49-17-12 and49-17-13, which are group 17 compounds in groups 17-1 through 17-13, (4)groups 49-15-14-1, 49-15-14-2, 49-15-14-3, 49-15-14-4, 49-15-14-5,49-15-14-5A, 49-15-14-6, 49-15-14-7, 49-15-14-8, 49-15-14-8A,49-15-14-9, 49-15-14-10, 49-15-14-10A, 49-15-14-11, 49-15-14-12 and49-15-14-13, which are group 15 compounds in groups 15-14-1 through15-14-13, (5) groups 49-16-14-1, 49-16-14-2, 49-16-14-3, 49-16-14-4,49-16-14-5, 49-16-14-5A, 49-16-14-6, 49-16-14-7, 49-16-14-8,49-16-14-8A, 49-16-14-9, 49-16-14-10, 49-16-14-10A, 49-16-14-11,49-16-14-12 and 49-16-14-13, which are group 16 compounds in groups16-14-1 through 16-14-13, (6) groups 49-17-14-1, 49-17-14-2, 49-17-14-3,49-17-14-4, 49-17-14-5, 49-17-14-5A, 49-17-14-6, 49-17-14-7, 49-17-14-8,49-17-14-8A, 49-17-14-9, 49-17-14-10, 49-17-14-10A, 49-17-14-11,49-17-14-12, 49-17-14-13, which are group 17 compounds in groups 17-14-1through 17-14-13, (7) groups 49-16-15-1, 49-16-15-2, 49-16-15-3,49-16-15-4, 49-16-15-5, 49-16-15-5A, 49-16-15-6, 49-16-15-7, 49-16-15-8,49-16-15-8A, 49-16-15-9, 49-16-15-10, 49-16-15-10A, 49-16-15-11,49-16-15-12, 49-16-15-13, which are group 16 compounds in groups 16-15-1through 16-15-13, (8) groups 49-17-15-1, 49-17-15-2, 49-17-15-3,49-17-15-4, 49-17-15-5, 49-17-15-5A, 49-17-15-6, 49-17-15-7, 49-17-15-8,49-17-15-8A, 49-17-15-9, 49-17-15-10, 49-17-15-10A, 49-17-15-11,49-17-15-12, 49-17-15-13, which are group 17 compounds in groups 17-15-1through 17-15-13, (9) groups 49-17-16-1, 49-17-16-2, 49-17-16-3,49-17-16-4, 49-17-16-5, 49-17-16-5A, 49-17-16-6, 49-17-16-7, 49-17-16-8,49-17-16-8A, 49-17-16-9, 49-17-16-10, 49-17-16-10A, 49-17-16-11,49-17-16-12, 49-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13, (10) groups 49-16-15-14-1, 49-16-15-14-2,49-16-15-14-3, 49-16-15-14-4, 49-16-15-14-5, 49-16-15-14-5A,49-16-15-14-6, 49-16-15-14-7, 49-16-15-14-8, 49-16-15-14-8A,49-16-15-14-9, 49-16-15-14-10, 49-16-15-14-10A, 49-16-15-14-11,49-16-15-14-12, 49-16-15-14-13, which are group 16 compounds in groups16-15-14-1 through 16-15-14-13, (11) groups 49-17-15-14-1,49-17-15-14-2, 49-17-15-14-3, 49-17-15-14-4, 49-17-15-14-5,49-17-15-14-5A, 49-17-15-14-6, 49-17-15-14-7, 49-17-15-14-8,49-17-15-14-8A, 49-17-15-14-9, 49-17-15-14-10, 49-17-15-14-10A,49-17-15-14-11, 49-17-15-14-12, 49-17-15-14-13, which are group 17compounds in groups 17-15-14-1 through 17-15-14-13, (12) groups49-17-16-14-1, 49-17-16-14-2, 49-17-16-14-3, 49-17-16-14-4,49-17-16-14-5, 49-17-16-14-5A, 49-17-16-14-6, 49-17-16-14-7,49-17-16-14-8, 49-17-16-14-8A, 49-17-16-14-9, 49-17-16-14-10,49-17-16-14-10A, 49-17-16-14-11, 49-17-16-14-12, 49-17-16-14-13, whichare group 17 compounds in groups 17-16-14-1 through 17-15-14-13, (13)groups 49-17-16-15-1, 49-17-16-15-2, 49-17-16-15-3, 49-17-16-15-4,49-17-16-15-5, 49-17-16-15-5A, 49-17-16-15-6, 49-17-16-15-7,49-17-16-15-8, 49-17-16-15-8A, 49-17-16-15-9, 49-17-16-15-10,49-17-16-15-10A, 49-17-16-15-11, 49-17-16-15-12 and 49-17-16-15-13,which are group 17 compounds in groups 17-16-15-1 through 17-16-15-13,(14) groups 49-17-16-15-14-1, 49-17-16-15-14-2, 49-17-16-15-14-3,49-17-16-15-14-4, 49-17-16-15-14-5, 49-17-16-15-14-5A, 49-17-16-15-14-6,49-17-16-15-14-7, 49-17-16-15-14-8, 49-17-16-15-14-8A, 49-17-16-15-14-9,49-17-16-15-14-10, 49-17-16-15-14-10A, 49-17-16-15-14-11,49-17-16-15-14-12 and 49-17-16-15-14-13, which are group 17 compounds ingroups 17-16-15-14-1 through 17-16-15-14-13, (15) all of the compoundsand/or groups described in group 18, (16) all of the compounds and/orgroups described in group 19, (17) all of the compounds and/or groupsdescribed in group 20, (18) all of the compounds and/or groups describedin groups 21, 22, 23, 24, 25, 26, 26A, 26B, 26C, 26E and 27, (19) all ofthe compounds and/or groups described in groups 28, 29, 30, 31, 32, 33,33A, 33B, 33C, 33D, 33E and 34, (20) all of the compounds and/or groupsdescribed in groups 35, 36, 37, 38, 39, 40, 40A, 40B, 40C, 40D, 40E and41 and (21) all of the compounds and/or groups described in groups 42,43, 44, 45, 46, 47, 47A, 47B, 47C, 47D, 47E, and 48.

Group 50. This group contains compounds in groups 1-49 above wherein R¹is single bonded and a second R¹ that is not —H is present. The secondR¹ can be a moiety defined herein for R¹, e.g., optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,halogen, ester, —OH, —CH₃, —C₂H₅, —C₃H₇, —CN, —C≡CH, —C≡C-halogen,—C≡C—OH, —C≡C—CH₃, —C═CH₂, —CH₂—C═CH₂, —NH₂, —SH or —OH.

These compounds include compounds in group 50-1 through50-49-48-41-34-27-20-19-18-17-16-15-14-13, which collectively are group50 compounds. These include groups 50-1, 50-2, 50-3, 50-4, 50-5, 50-5A,50-6, 50-7, 50-8, 50-8A, 50-9, 50-10, 50-10A, 50-11, 50-12, 50-13, whichare compounds in groups 1 through 13 where a second R¹ substituent ispresent. Group 50 compounds also include groups 50-14-1, 50-14-2,50-14-3, 50-14-4, 50-14-5, 50-14-5A, 50-14-6, 50-14-7, 50-14-8,50-14-8A, 50-14-9, 50-14-10, 50-14-10A, 50-14-11, 50-14-12 and 50-14-13,which are group 14 compounds in groups 14-1 through 14-13 where a secondR¹ substituent is present.

Other group 50 compounds include (1) groups 50-15-1, 50-15-2, 50-15-3,50-15-4, 50-15-5, 50-15-5A, 50-15-6, 50-15-7, 50-15-8, 50-15-8A,50-15-9, 50-15-10, 50-15-10A, 50-15-11, 50-15-12 and 50-15-13, which aregroup 15 compounds in groups 15-1 through 15-13, (2) groups 50-16-1,50-16-2, 50-16-3, 50-16-4, 50-16-5, 50-16-5A, 50-16-6, 50-16-7, 50-16-8,50-16-8A, 50-16-9, 50-16-10, 50-16-10A, 50-16-11, 50-16-12 and 50-16-13,which are group 16 compounds in groups 16-1 through 16-13, (3) groups50-17-1, 50-17-2, 50-17-3, 50-17-4, 50-17-5, 50-17-5A, 50-17-6, 50-17-7,50-17-8, 50-17-8A, 50-17-9, 50-17-10, 50-17-10A, 50-17-11, 50-17-12 and50-17-13, which are group 17 compounds in groups 17-1 through 17-13, (4)groups 50-15-14-1, 50-15-14-2, 50-15-14-3, 50-15-14-4, 50-15-14-5,50-15-14-5A, 50-15-14-6, 50-15-14-7, 50-15-14-8, 50-15-14-8A,50-15-14-9, 50-15-14-10, 50-15-14-10A, 50-15-14-11, 50-15-14-12 and50-15-14-13, which are group 15 compounds in groups 15-14-1 through15-14-13, (5) groups 50-16-14-1, 50-16-14-2, 50-16-14-3, 50-16-14-4,50-16-14-5, 50-16-14-5A, 50-16-14-6, 50-16-14-7, 50-16-14-8,50-16-14-8A, 50-16-14-9, 50-16-14-10, 50-16-14-10A, 50-16-14-11,50-16-14-12 and 50-16-14-13, which are group 16 compounds in groups16-14-1 through 16-14-13, (6) groups 50-17-14-1, 50-17-14-2, 50-17-14-3,50-17-14-4, 50-17-14-5, 50-17-14-5A, 50-17-14-6, 50-17-14-7, 50-17-14-8,50-17-14-8A, 50-17-14-9, 50-17-14-10, 50-17-14-10A, 50-17-14-11,50-17-14-12, 50-17-14-13, which are group 17 compounds in groups 17-14-1through 17-14-13, (7) groups 50-16-15-1, 50-16-15-2, 50-16-15-3,50-16-15-4, 50-16-15-5, 50-16-15-5A, 50-16-15-6, 50-16-15-7, 50-16-15-8,50-16-15-8A, 50-16-15-9, 50-16-15-10, 50-16-15-10A, 50-16-15-11,50-16-15-12, 50-16-15-13, which are group 16 compounds in groups 16-15-1through 16-15-13, (8) groups 50-17-15-1, 50-17-15-2, 50-17-15-3,50-17-15-4, 50-17-15-5, 50-17-15-5A, 50-17-15-6, 50-17-15-7, 50-17-15-8,50-17-15-8A, 50-17-15-9, 50-17-15-10, 50-17-15-10A, 50-17-15-11,50-17-15-12, 50-17-15-13, which are group 17 compounds in groups 17-15-1through 17-15-13, (9) groups 50-17-16-1, 50-17-16-2, 50-17-16-3,50-17-16-4, 50-17-16-5, 50-17-16-5A, 50-17-16-6, 50-17-16-7, 50-17-16-8,50-17-16-8A, 50-17-16-9, 50-17-16-10, 50-17-16-10A, 50-17-16-11,50-17-16-12, 50-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13, (10) groups 50-16-15-14-1, 50-16-15-14-2,50-16-15-14-3, 50-16-15-14-4, 50-16-15-14-5, 50-16-15-14-5A,50-16-15-14-6, 50-16-15-14-7, 50-16-15-14-8, 50-16-15-14-8A,50-16-15-14-9, 50-16-15-14-10, 50-16-15-14-10A, 50-16-15-14-11,50-16-15-14-12, 50-16-15-14-13, which are group 16 compounds in groups16-15-14-1 through 16-15-14-13, (11) groups 50-17-15-14-1,50-17-15-14-2, 50-17-15-14-3, 50-17-15-14-4, 50-17-15-14-5,50-17-15-14-5A, 50-17-15-14-6, 50-17-15-14-7, 50-17-15-14-8,50-17-15-14-8A, 50-17-15-14-9, 50-17-15-14-10, 50-17-15-14-10A,50-17-15-14-11, 50-17-15-14-12, 50-17-15-14-13, which are group 17compounds in groups 17-15-14-1 through 17-15-14-13, (12) groups50-17-16-14-1, 50-17-16-14-2, 50-17-16-14-3, 50-17-16-14-4,50-17-16-14-5, 50-17-16-14-5A, 50-17-16-14-6, 50-17-16-14-7,50-17-16-14-8, 50-17-16-14-8A, 50-17-16-14-9, 50-17-16-14-10,50-17-16-14-10A, 50-17-16-14-11, 50-17-16-14-12, 50-17-16-14-13, whichare group 17 compounds in groups 17-16-14-1 through 17-15-14-13, (13)groups 50-17-16-15-1, 50-17-16-15-2, 50-17-16-15-3, 50-17-16-15-4,50-17-16-15-5, 50-17-16-15-5A, 50-17-16-15-6, 50-17-16-15-7,50-17-16-15-8, 50-17-16-15-8A, 50-17-16-15-9, 50-17-16-15-10,50-17-16-15-10A, 50-17-16-15-11, 50-17-16-15-12 and 50-17-16-15-13,which are group 17 compounds in groups 17-16-15-1 through 17-16-15-13,(14) groups 50-17-16-15-14-1, 50-17-16-15-14-2, 50-17-16-15-14-3,50-17-16-15-14-4, 50-17-16-15-14-5, 50-17-16-15-14-5A, 50-17-16-15-14-6,50-17-16-15-14-7, 50-17-16-15-14-8, 50-17-16-15-14-8A, 50-17-16-15-14-9,50-17-16-15-14-10, 50-17-16-15-14-10A, 50-17-16-15-14-11,50-17-16-15-14-12 and 50-17-16-15-14-13, which are group 17 compounds ingroups 17-16-15-14-1 through 17-16-15-14-13, (15) all of the compoundsand/or groups described in group 18, (16) all of the compounds and/orgroups described in group 19, (17) all of the compounds and/or groupsdescribed in group 20, (18) all of the compounds and/or groups describedin groups 21, 22, 23, 24, 25, 26, 26A, 26B, 26C, 26E and 27, (19) all ofthe compounds and/or groups described in groups 28, 29, 30, 31, 32, 33,33A, 33B, 33C, 33D, 33E and 34, (20) all of the compounds and/or groupsdescribed in groups 35, 36, 37, 38, 39, 40, 40A, 40B, 40C, 40D, 40E and41 and (21) all of the compounds and/or groups described in groups 42,43, 44, 45, 46, 47, 47A, 47B, 47C, 47D, 47E, 48 and 49.

Group 51. This group contains compounds in groups 1-50 above wherein R³is single bonded and a second R³ that is not —H is present. The secondR³ can be a moiety defined herein for R³, e.g., optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,halogen, ester, —OH, —CH₃, —C₂H₅, —C₃H₇, —CN, —C≡CH, —C≡C-halogen,—C≡C—OH, —C≡C—CH₃, —C═CH₂, —CH₂—C═CH₂, —NH₂, —SH or —OH.

These compounds include compounds in group 51-1 through51-49-48-41-34-27-20-19-18-17-16-15-14-13, which collectively are group51 compounds. These include groups 51-1, 51-2, 51-3, 51-4, 51-5, 51-5A,51-6, 51-7, 51-8, 51-8A, 51-9, 51-10, 51-10A, 51-11, 51-12, 51-13, whichare compounds in groups 1 through 13 where a second R³ substituent ispresent. Group 51 compounds also include groups 51-14-1, 51-14-2,51-14-3, 51-14-4, 51-14-5, 51-14-5A, 51-14-6, 51-14-7, 51-14-8,51-14-8A, 51-14-9, 51-14-10, 51-14-10A, 51-14-11, 51-14-12 and 51-14-13,which are group 14 compounds in groups 14-1 through 14-13 where a secondR³ substituent is present.

Other group 51 compounds include (1) groups 51-15-1, 51-15-2, 51-15-3,51-15-4, 51-15-5, 51-15-5A, 51-15-6, 51-15-7, 51-15-8, 51-15-8A,51-15-9, 51-15-10, 51-15-10A, 51-15-11, 51-15-12 and 51-15-13, which aregroup 15 compounds in groups 15-1 through 15-13, (2) groups 51-16-1,51-16-2, 51-16-3, 51-16-4, 51-16-5, 51-16-5A, 51-16-6, 51-16-7, 51-16-8,51-16-8A, 51-16-9, 51-16-10, 51-16-10A, 51-16-11, 51-16-12 and 51-16-13,which are group 16 compounds in groups 16-1 through 16-13, (3) groups51-17-1, 51-17-2, 51-17-3, 51-17-4, 51-17-5, 51-17-5A, 51-17-6, 51-17-7,51-17-8, 51-17-8A, 51-17-9, 51-17-10, 51-17-10A, 51-17-11, 51-17-12 and51-17-13, which are group 17 compounds in groups 17-1 through 17-13, (4)groups 51-15-14-1, 51-15-14-2, 51-15-14-3, 51-15-14-4, 51-15-14-5,51-15-14-5A, 51-15-14-6, 51-15-14-7, 51-15-14-8, 51-15-14-8A,51-15-14-9, 51-15-14-10, 51-15-14-10A, 51-15-14-11, 51-15-14-12 and51-15-14-13, which are group 15 compounds in groups 15-14-1 through15-14-13, (5) groups 51-16-14-1, 51-16-14-2, 51-16-14-3, 51-16-14-4,51-16-14-5, 51-16-14-5A, 51-16-14-6, 51-16-14-7, 51-16-14-8,51-16-14-8A, 51-16-14-9, 51-16-14-10, 51-16-14-10A, 51-16-14-11,51-16-14-12 and 51-16-14-13, which are group 16 compounds in groups16-14-1 through 16-14-13, (6) groups 51-17-14-1, 51-17-14-2, 51-17-14-3,51-17-14-4, 51-17-14-5, 51-17-14-5A, 51-17-14-6, 51-17-14-7, 51-17-14-8,51-17-14-8A, 51-17-14-9, 51-17-14-10, 51-17-14-10A, 51-17-14-11,51-17-14-12, 51-17-14-13, which are group 17 compounds in groups 17-14-1through 17-14-13, (7) groups 51-16-15-1, 51-16-15-2, 51-16-15-3,51-16-15-4, 51-16-15-5, 51-16-15-5A, 51-16-15-6, 51-16-15-7, 51-16-15-8,51-16-15-8A, 51-16-15-9, 51-16-15-10, 51-16-15-10A, 51-16-15-11,51-16-15-12, 51-16-15-13, which are group 16 compounds in groups 16-15-1through 16-15-13, (8) groups 51-17-15-1, 51-17-15-2, 51-17-15-3,51-17-15-4, 51-17-15-5, 51-17-15-5A, 51-17-15-6, 51-17-15-7, 51-17-15-8,51-17-15-8A, 51-17-15-9, 51-17-15-10, 51-17-15-10A, 51-17-15-11,51-17-15-12, 51-17-15-13, which are group 17 compounds in groups 17-15-1through 17-15-13, (9) groups 51-17-16-1, 51-17-16-2, 51-17-16-3,51-17-16-4, 51-17-16-5, 51-17-16-5A, 51-17-16-6, 51-17-16-7, 51-17-16-8,51-17-16-8A, 51-17-16-9, 51-17-16-10, 51-17-16-10A, 51-17-16-11,51-17-16-12, 51-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13, (10) groups 51-16-15-14-1, 51-16-15-14-2,51-16-15-14-3, 51-16-15-14-4, 51-16-15-14-5, 51-16-15-14-5A,51-16-15-14-6, 51-16-15-14-7, 51-16-15-14-8, 51-16-15-14-8A,51-16-15-14-9, 51-16-15-14-10, 51-16-15-14-10A, 51-16-15-14-11,51-16-15-14-12, 51-16-15-14-13, which are group 16 compounds in groups16-15-14-1 through 16-15-14-13, (11) groups 51-17-15-14-1,51-17-15-14-2, 51-17-15-14-3, 51-17-15-14-4, 51-17-15-14-5,51-17-15-14-5A, 51-17-15-14-6, 51-17-15-14-7, 51-17-15-14-8,51-17-15-14-8A, 51-17-15-14-9, 51-17-15-14-10, 51-17-15-14-10A,51-17-15-14-11, 51-17-15-14-12, 51-17-15-14-13, which are group 17compounds in groups 17-15-14-1 through 17-15-14-13, (12) groups51-17-16-14-1, 51-17-16-14-2, 51-17-16-14-3, 51-17-16-14-4,51-17-16-14-5, 51-17-16-14-5A, 51-17-16-14-6, 51-17-16-14-7,51-17-16-14-8, 51-17-16-14-8A, 51-17-16-14-9, 51-17-16-14-10,51-17-16-14-10A, 51-17-16-14-11, 51-17-16-14-12, 51-17-16-14-13, whichare group 17 compounds in groups 17-16-14-1 through 17-15-14-13, (13)groups 51-17-16-15-1, 51-17-16-15-2, 51-17-16-15-3, 51-17-16-15-4,51-17-16-15-5, 51-17-16-15-5A, 51-17-16-15-6, 51-17-16-15-7,51-17-16-15-8, 51-17-16-15-8A, 51-17-16-15-9, 51-17-16-15-10,51-17-16-15-10A, 51-17-16-15-11, 51-17-16-15-12 and 51-17-16-15-13,which are group 17 compounds in groups 17-16-15-1 through 17-16-15-13,(14) groups 51-17-16-15-14-1, 51-17-16-15-14-2, 51-17-16-15-14-3,51-17-16-15-14-4, 51-17-16-15-14-5, 51-17-16-15-14-5A, 51-17-16-15-14-6,51-17-16-15-14-7, 51-17-16-15-14-8, 51-17-16-15-14-8A, 51-17-16-15-14-9,51-17-16-15-14-10, 51-17-16-15-14-10A, 51-17-16-15-14-11,51-17-16-15-14-12 and 51-17-16-15-14-13, which are group 17 compounds ingroups 17-16-15-14-1 through 17-16-15-14-13, (15) all of the compoundsand/or groups described in group 18, (16) all of the compounds and/orgroups described in group 19, (17) all of the compounds and/or groupsdescribed in group 20, (18) all of the compounds and/or groups describedin groups 21, 22, 23, 24, 25, 26, 26A, 26B, 26C, 26E and 27, (19) all ofthe compounds and/or groups described in groups 28, 29, 30, 31, 32, 33,33A, 33B, 33C, 33D, 33E and 34, (20) all of the compounds and/or groupsdescribed in groups 35, 36, 37, 38, 39, 40, 40A, 40B, 40C, 40D, 40E and41 and (21) all of the compounds and/or groups described in groups 42,43, 44, 45, 46, 47, 47A, 47B, 47C, 47D, 47E, 48, 49 and 50.

Group 52. This group contains compounds in groups 1-51 above wherein R²is single bonded and a second R² that is not —H is present. The secondR² can be a moiety defined herein for R², e.g., optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,halogen, ester, —OH, —CH₃, —C₂H₅, —C₃H₇, —CN, —C≡CH, —C≡C-halogen,—C≡C—OH, —C≡C—CH₃, —C═CH₂, —CH₂—C═CH₂, —NH₂, —SH or —OH.

These compounds include compounds in group 52-1 through52-51-49-48-41-34-27-20-19-18-17-16-15-14-13, which collectively aregroup 52 compounds. These include groups 52-1, 52-2, 52-3, 52-4, 52-5,52-5A, 52-6, 52-7, 52-8, 52-8A, 52-9, 52-10, 52-10A, 52-11, 52-12,52-13, which are compounds in groups 1 through 13 where a second R²substituent is present. Group 52 compounds also include groups 52-14-1,52-14-2, 52-14-3, 52-14-4, 52-14-5, 52-14-5A, 52-14-6, 52-14-7, 52-14-8,52-14-8A, 52-14-9, 52-14-10, 52-14-10A, 52-14-11, 52-14-12 and 52-14-13,which are group 14 compounds in groups 14-1 through 14-13 where a secondR² substituent is present.

Other group 52 compounds include (1) groups 52-15-1, 52-15-2, 52-15-3,52-15-4, 52-15-5, 52-15-5A, 52-15-6, 52-15-7, 52-15-8, 52-15-8A,52-15-9, 52-15-10, 52-15-10A, 52-15-11, 52-15-12 and 52-15-13, which aregroup 15 compounds in groups 15-1 through 15-13, (2) groups 52-16-1,52-16-2, 52-16-3, 52-16-4, 52-16-5, 52-16-5A, 52-16-6, 52-16-7, 52-16-8,52-16-8A, 52-16-9, 52-16-10, 52-16-10A, 52-16-11, 52-16-12 and 52-16-13,which are group 16 compounds in groups 16-1 through 16-13, (3) groups52-17-1, 52-17-2, 52-17-3, 52-17-4, 52-17-5, 52-17-5A, 52-17-6, 52-17-7,52-17-8, 52-17-8A, 52-17-9, 52-17-10, 52-17-10A, 52-17-11, 52-17-12 and52-17-13, which are group 17 compounds in groups 17-1 through 17-13, (4)groups 52-15-14-1, 52-15-14-2, 52-15-14-3, 52-15-14-4, 52-15-14-5,52-15-14-5A, 52-15-14-6, 52-15-14-7, 52-15-14-8, 52-15-14-8A,52-15-14-9, 52-15-14-10, 52-15-14-10A, 52-15-14-11, 52-15-14-12 and52-15-14-13, which are group 15 compounds in groups 15-14-1 through15-14-13, (5) groups 52-16-14-1, 52-16-14-2, 52-16-14-3, 52-16-14-4,52-16-14-5, 52-16-14-5A, 52-16-14-6, 52-16-14-7, 52-16-14-8,52-16-14-8A, 52-16-14-9, 52-16-14-10, 52-16-14-10A, 52-16-14-11,52-16-14-12 and 52-16-14-13, which are group 16 compounds in groups16-14-1 through 16-14-13, (6) groups 52-17-14-1, 52-17-14-2, 52-17-14-3,52-17-14-4, 52-17-14-5, 52-17-14-5A, 52-17-14-6, 52-17-14-7, 52-17-14-8,52-17-14-8A, 52-17-14-9, 52-17-14-10, 52-17-14-10A, 52-17-14-11,52-17-14-12, 52-17-14-13, which are group 17 compounds in groups 17-14-1through 17-14-13, (7) groups 52-16-15-1, 52-16-15-2, 52-16-15-3,52-16-15-4, 52-16-15-5, 52-16-15-5A, 52-16-15-6, 52-16-15-7, 52-16-15-8,52-16-15-8A, 52-16-15-9, 52-16-15-10, 52-16-15-10A, 52-16-15-11,52-16-15-12, 52-16-15-13, which are group 16 compounds in groups 16-15-1through 16-15-13, (8) groups 52-17-15-1, 52-17-15-2, 52-17-15-3,52-17-15-4, 52-17-15-5, 52-17-15-5A, 52-17-15-6, 52-17-15-7, 52-17-15-8,52-17-15-8A, 52-17-15-9, 52-17-15-10, 52-17-15-10A, 52-17-15-11,52-17-15-12, 52-17-15-13, which are group 17 compounds in groups 17-15-1through 17-15-13, (9) groups 52-17-16-1, 52-17-16-2, 52-17-16-3,52-17-16-4, 52-17-16-5, 52-17-16-5A, 52-17-16-6, 52-17-16-7, 52-17-16-8,52-17-16-8A, 52-17-16-9, 52-17-16-10, 52-17-16-10A, 52-17-16-11,52-17-16-12, 52-17-16-13, which are group 17 compounds in groups 17-16-1through 17-16-13, (10) groups 52-16-15-14-1, 52-16-15-14-2,52-16-15-14-3, 52-16-15-14-4, 52-16-15-14-5, 52-16-15-14-5A,52-16-15-14-6, 52-16-15-14-7, 52-16-15-14-8, 52-16-15-14-8A,52-16-15-14-9, 52-16-15-14-10, 52-16-15-14-10A, 52-16-15-14-11,52-16-15-14-12, 52-16-15-14-13, which are group 16 compounds in groups16-15-14-1 through 16-15-14-13, (11) groups 52-17-15-14-1,52-17-15-14-2, 52-17-15-14-3, 52-17-15-14-4, 52-17-15-14-5,52-17-15-14-5A, 52-17-15-14-6, 52-17-15-14-7, 52-17-15-14-8,52-17-15-14-8A, 52-17-15-14-9, 52-17-15-14-10, 52-17-15-14-10A,52-17-15-14-11, 52-17-15-14-12, 52-17-15-14-13, which are group 17compounds in groups 17-15-14-1 through 17-15-14-13, (12) groups52-17-16-14-1, 52-17-16-14-2, 52-17-16-14-3, 52-17-16-14-4,52-17-16-14-5, 52-17-16-14-5A, 52-17-16-14-6, 52-17-16-14-7,52-17-16-14-8, 52-17-16-14-8A, 52-17-16-14-9, 52-17-16-14-10,52-17-16-14-10A, 52-17-16-14-11, 52-17-16-14-12, 52-17-16-14-13, whichare group 17 compounds in groups 17-16-14-1 through 17-15-14-13, (13)groups 52-17-16-15-1, 52-17-16-15-2, 52-17-16-15-3, 52-17-16-15-4,52-17-16-15-5, 52-17-16-15-5A, 52-17-16-15-6, 52-17-16-15-7,52-17-16-15-8, 52-17-16-15-8A, 52-17-16-15-9, 52-17-16-15-10,52-17-16-15-10A, 52-17-16-15-11, 52-17-16-15-12 and 52-17-16-15-13,which are group 17 compounds in groups 17-16-15-1 through 17-16-15-13,(14) groups 52-17-16-15-14-1, 52-17-16-15-14-2, 52-17-16-15-14-3,52-17-16-15-14-4, 52-17-16-15-14-5, 52-17-16-15-14-5A, 52-17-16-15-14-6,52-17-16-15-14-7, 52-17-16-15-14-8, 52-17-16-15-14-8A, 52-17-16-15-14-9,52-17-16-15-14-10, 52-17-16-15-14-10A, 52-17-16-15-14-11,52-17-16-15-14-12 and 52-17-16-15-14-13, which are group 17 compounds ingroups 17-16-15-14-1 through 17-16-15-14-13, (15) all of the compoundsand/or groups described in group 18, (16) all of the compounds and/orgroups described in group 19, (17) all of the compounds and/or groupsdescribed in group 20, (18) all of the compounds and/or groups describedin groups 21, 22, 23, 24, 25, 26, 26A, 26B, 26C, 26E and 27, (19) all ofthe compounds and/or groups described in groups 28, 29, 30, 31, 32, 33,33A, 33B, 33C, 33D, 33E and 34, (20) all of the compounds and/or groupsdescribed in groups 35, 36, 37, 38, 39, 40, 40A, 40B, 40C, 40D, 40E and41 and (21) all of the compounds and/or groups described in groups 42,43, 44, 45, 46, 47, 47A, 47B, 47C, 47D, 47E, 48, 49, 50 and 51.

As is apparent from the foregoing description of F1Cs in groups 1through 52, compound groups 14 through 52 contain a number of definedsubgroups, e.g., group 14-3 is a subgroup as described for group 14compounds where R¹, R², R³ and R⁴ can be in the configurations describedin group 14, e.g., α,β,α,β, α,α,α,β, β,β,β,β, β,β,β,α or β,β,α,αrespectively. Similarly, group 49 includes subgroups such as49-18-17-14-3, 49-18-17-14-4, 49-18-17-14-5, 49-18-17-14-5A,49-18-17-14-6, 49-18-17-14-7 and 49-18-17-14-9, which are subgroupswhere R⁹ is substituted, e.g., R⁹ is —O— or a moiety described in group18, and such subgroups, although not specifically named or described,are expressly included in group 49. The F1C therefore include allpossible subgroups in each group, regardless of whether each subgroup isspecifically named or described in a given group or not. For example,groups such as 22, 23, 26, 26B, 26C, 26D and 26E, all include subgroupsanalogous to those described in group 26A and additional subgroups thatare not expressly described, e.g., subgroups such as 26-18-1, 26-18-2,26-18-3, 26-18-4, 26-18-5, 26-18-5A, 26-18-6, 26-18-14-1, 26-18-14-2,26-18-14-3, 26-18-14-4, 26-18-14-5, 26-18-14-5A and 26-18-14-6 are notdescribed expressly in group 26 above, but are included in group 26.Similarly, groups 29, 30, 33, 33B, 33C, 33D and 33E, all includesubgroups analogous to those described in group 33A, while groups 36,37, 40B, 40C, 40D, 40E and 41 all include subgroups analogous to thosedescribed in group 40A and groups 47B, 47C, 47D, 47E and 48 all includesubgroups analogous to those described in group 47A. Thus, subgroupssuch as 33-18-3 and 33-18-14-3, which are not described expressly ingroup 33 above, are included in group 33.

As is apparent from the definitions provided herein, the F1Cs alsoinclude analogs of the compounds in groups 1 through 52. Exemplaryanalogs include compounds where R^(10G) and/or R^(10H) is a moiety otherthan hydrogen, e.g., halogen or optionally substituted alkyl such as —F,—Cl, —Br, —I, —CH₃, —OH, —NH₂ or —SH. Thus, for any of the compounds orgenera of compounds in groups 1 through 52, R^(10G) can be —F or —Cl inthe α- or β-configuration. Similarly, in groups 1 through 52, R^(10H)can be —F, —NH₂ or —OH in the α- or β-configuration or an epoxide orcyclopropyl ring with R⁷ α- or β-configuration.

Metabolites. The invention includes the therapeutic or other usesdisclosed herein of metabolites of F1C, which include biologicallyactive metabolites. Metabolites can arise from in vivo or in vitrometabolism. Metabolites of F1C include products that are new.Metabolites may result for example from the oxidation, reduction,hydrolysis, amidation, esterification, glycosidation and the like of theadministered formula 1 compound, due to enzymatic or chemical processes.Metabolites may be generated in vivo in a subject or they may arise exvivo from cells or tissues, e.g., from a mammal such as a human, rodentor a primate. Accordingly, the invention includes new F1Cs produced by aprocess comprising contacting an F1C with a subject or a subject's cellsor tissue for a period of time sufficient to yield detectable amounts ofa metabolic product thereof. Such products typically are identified bypreparing a radiolabeled or mass labeled F1C that comprises, e.g., 1, 2,3 or more ¹³C, ¹⁴C, ³H, ²H, ¹³¹I, ³²P, ³⁵S or ⁹⁹Tc atoms bonded to thecompound, and administering it as a trace labeled compound along withthe unlabeled compound. The labeled and unlabeled compounds areadministered by any suitable route (by, e.g., a buccal, sublingual,parenteral, topical or oral route) in a detectable dose (e.g. greaterthan about 0.1 μg/kg, or at least about 10 μg/kg or at least about 0.5mg/kg of the labeled compound) to a subject, e.g., an animal or mammalsuch as rat, mouse, guinea pig, primate, or to a human. Afteradministration sufficient time is allowed for metabolism to occur(typically about 30 seconds to 30 hours) and conversion products areisolated from one or more of the urine, blood, plasma, feces or othersuitable biological sources. The amount of labeled formula 1 compoundthat is administered to a subject will vary with the specific activityof the labeled compound. Exemplary metabolic conversions of formula 1compounds include modification of hydrogen atoms or other moieties thatare bonded to, e.g., one or more of the 1, 2, 3, 4, 6, 7, 11, 15, 16 or17 positions. Exemplary conversions at these one or more of positionsinclude hydroxylation of ring atoms, e.g., ring carbon atoms,conjugation of hydroxyl groups that are bonded to one or more of thosepositions with moieties such as sulfate, phosphate or a monosaccharideor disaccharide such as glucuronic acid and hydrolysis of moieties suchas esters or alkoxy groups.

Analytical characterization and reference standards. Individual F1Csdescribed or disclosed herein are suitable for use as standards fordetermining chemical or physical properties using one, two or moreanalytical methods, e.g., for use in HPLC, reverse phase HPLC, MS (massspectrometry), quadrupole MS, GC-MS, LC-MS, NMR (nuclear magneticresonance spectrometry), ²H-NMR, ³H-NMR, ¹³C-NMR, ¹⁴C-NMR, infraredspectrometry (IR), Fourier transform-IR, optical rotary dispersion, losson drying for water and solvent measurement, Karl Fisher titration forwater determination, differential scanning calorimetry, melting point,density, refractive index, solubility characteristics in organicsolvents, aqueous systems or aqueous-organic solvent mixtures, thepartition coefficient in immiscible solvent systems, e.g., octanol:waterpartition coefficient, heat stability or epimerization rate orcharacteristics of a given enantiomer. These analytical or chemicalproperties of each F1C are collectively referred to as analyticalcharacteristics. For general methods, see, e.g., H. L. J. Makin et al.,eds. Steroid Analysis 1995, Chapman & Hall, ISBN 0751401285. Thus, toaid in the determination of, e.g., the structure of a metabolite of aF1C or a structurally related compound, the parent compound or anotherstructurally related F1C could be used as a standard. Metabolism of F1Cswill often include one or more of oxidation, reduction, hydroxylation orconjugation, e.g., oxidation or reduction to a —OH or ═O moiety, orconjugation with a moiety such as sulfate, phosphate, amino acid,dipeptide or a monosaccharide such as glucuronic acid at, e.g., the 2,3, 6, 7, 11, 15, 16, 17 or other positions on the steroid nucleus. Inthese embodiments, the appropriate use of a F1C of known structure as astandard can aid in or verify the identification of metabolites that areprojected to have closely related structures. Information regarding theidentification can be useful or sometimes is necessary for, e.g.,obtaining regulatory approval to market a therapeutic agent such as aF1C or understanding the potential biological role that a F1C or itsmetabolite can play in one of the applications disclosed herein or in acited reference. To facilitate such uses, the F1C may be labeled asappropriate, e.g., using a F1C with, e.g., one or more ²H, ³H, ¹³C, ¹⁴C,¹⁵N, ¹⁸O, ¹⁸F, ³⁵S, ³²P or ¹²³I, at 1, 2 or more of the 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or otherpositions in any formula 1 steroid. Radiolabel or heavy isotope atomsmay be directly bonded to, or for carbon atoms, replace a steroidnucleus atom, or they may be bonded through one, two or more interveningatoms, e.g., steroid-O—³²P(O)(OH)(OH). Suitably labeled compoundsinclude any of the F1Cs disclosed herein. Such labeled compounds maycomprise, e.g., a ¹³C at the 18 or 19 positions and 1, 2, 3 or 4 ³H maybe bonded to the ¹³C atom(s) or to a ring carbon(s). Other formula 1compounds may comprise one or two ²H or ³H atoms bonded to one or moreof the 1, 2, 4, 5, 6, 11 or 12 positions and optionally a ¹³C at the 18or 19 position(s). F1Cs and their metabolites are isolated orcharacterized using radiolabeled or mass labeled atoms. F1Cs are alsooptionally isolated by the use of antibodies capable of binding toepitopes in F1Cs or in metabolites.

In general, analysis of F1C metabolites is accomplished in the same wayas conventional drug metabolism studies, which are known to thoseskilled in the art. The conversion products, especially when they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the formula 1 compounds even if they possess onlylimited therapeutic activity of their own.

Embodiments include a method (the “characterization method”) tocharacterize or at least partially characterize a formula 1 compoundthat is at least partially uncharacterized for one or more givenchemical or analytical properties, e.g., a known or potential metaboliteof a parent formula 1 compound, comprising (a) providing a formula 1compound having one, two or more known characteristics, e.g., a known orat least partially known or characterized chemical structure, XRDspectrum or melting point (a “CF1C”), and a formula 1 compound that isunknown or at least partially uncharacterized, i.e., is uncharacterizedfor at least one of the same analytical characteristics (a “UCF1C”), (b)obtaining one, two or more analytical characteristics of the UCF1C, and(c) comparing the 1, 2 or more analytical characteristics of the CF1Cwith the analytical characteristics of the UCF1C. The steps in thismethod may be conducted in any suitable order, e.g., analytical orchemical data for the CF1C will usually be obtained before or at aboutthe same time as one obtains the analytical or chemical data for theUCF1C. Usually the CF1C will be more completely characterized than theUCF1C, particularly with regard to its chemical structure or itsrelative degree of purity or with regard to the analytical or chemicaldata that is being sought. This method allows further characterizationof the UCF1C, e.g., by confirming the UCF1C's chemical structure or bydetermining the UCF1C's stability under various storage or temperatureconditions or in various formulations or by determining other analyticalor chemical properties of interest. In this method, the CF1C itself maynot be completely characterized, however, for the one, two or moreanalytical characteristics of interest, the CF1C will usually have aknown or confirmed property or properties, while the UCF1C is unknown orat least unconfirmed for the same property or properties.

In some embodiments the characterization method is conducted bycomparing dissimilar analytical characteristics. For example, the CF1Cmay be well characterized by GC-MS or by NMR, while an insufficientamount of the UCF1C is available for analysis with the same technique.In these cases, one can then, e.g., compare the GC-MS of the CF1C withthe NMR of the UCF1C to obtain the same or essentially the sameinformation for the UCF1C. Other examples of where this can be done iswhere DSC data is available for the CF1C, and only melting point data isavailable for the UCF1C. In this case, the CF1C DSC data is compared tothe UCF1C's melting point data. Also, in conducting the characterizationmethod, one can optionally derivatize or chemically modify the CF1Cand/or the UCF1C to facilitate analysis of the compound(s). For example,in conducting MS, GC-MS or NMR analysis, one or more free hydroxyl orketone moieties on the CF1C and/or the F2C can be silylated using, e.g.,trimethylsilyl chloride, t-butyl-dimethylsilyl chloride or othersuitable silylating agents. Similarly, the UCF1C may be treated orincubated with a cell line or tissue or with a glucuronidase, sulfatase,phosphatase, esterase, lipase, oxidoreductase or other enzyme and thencharacterized. This treatment may in some cases convert the UCF1C intothe CF1C, but this conversion would usually be confirmed by one, two ormore suitable analytical methods. Such treatments will usually generateadditional data about the structure, properties or origin of the UCF1C.

Embodiments include modifications of the characterization method thatuse a CF1C and a second formula 1 compound that is believed or known tohave a related structure or empirical formula. In these modifications,the CF1C is used as described and a second formula 1 compound or a UCF1Cthat is believed or known to be, e.g., an epimer or a salt, of the CF1Cis compared to the CF1C. Invention embodiments include othermodifications of the characterization method such as (1) comparinganalytical or chemical data from a single CF1C with 2, 3, 4 or moreUCF1C, (2) comparing analytical or chemical data from 2, 3, 4 or moreCF1C with a single UCF1C and (3) comparing analytical or chemical datafrom 2, 3, 4 or more CF1C with 2, 3, 4 or more UCF1C. In thesemodifications, the CF1C or UCF1C are used essentially as described forthe characterization method, except that data is obtained for the addedformula 1 compounds.

Typically, when the 1, 2 or more analytical characteristics of a CF1C ora UCF1C are obtained, which may be for use in the characterizationmethod or for other purposes, each compound is analyzed under the sameor essentially the same analytical conditions using the same oressentially the same analytical technique or instrument. Variations inan analytical technique may be used where the properties of a CF1C or aUCF1C require slightly different handling or specimen preparation. Anexample of a variation in analytical conditions is the comparison of aproperty of a CF1C, e.g., its stability to heat, humidity or prolongedstorage at a given temperature, with the same property of the CF1C in acomposition containing an excipient(s) or in a formulation (where theCF1C in a composition is then considered the UCF1C for thecharacterization method). This allows the determination of the stabilityof the CF1C as a pure compound compared to its stability in any desiredcomposition.

When characterizing a CF1C by MS, particularly by GC-MS, one willusually conduct an initial characterization of a formula 1 compound or aCF1C in the characterization method using a known GC-MS method (e.g., H.L. J. Makin et al., Mass Spectra and GC Data of Steroids: Androgens andEstrogens 1999 John Wiley & Sons, pages XIII-XIV) or a suitablevariation of this method. For F1Cs that contain free hydroxyls or oxogroups, the hydroxyl groups can be derivatized to an ester such asacetate, hydroxyl and oxo or groups can be derivatized to trimethylsilylether, i.e., —O—Si(CH₃)₃, and oxo groups can be derivatized to a anoxime such as ═N—O—CH₃ before GC-MS analysis. Other functional groupscan also be suitably derivatized. For embodiments of thecharacterization method that use a GC-MS analysis method, the CF1C orthe UCF1C is analyzed by the GC-MS method or a suitable variation toobtain or to confirm chemical structure information about the CF1C orthe UCF1C. Suitable variations include, e.g., a change in the carriergas from helium to hydrogen to increase the sensitivity of detection ora decrease in the ionization from 70 eV to 50 eV can give a betterparent mass ion.

As is apparent from the present disclosure, the F1C may be preparedsynthetically and typical embodiments will utilize purified a F1C.Purified F1C can be free, essentially free or partially free, of otherF1C or other compounds such as excipients. Thus, any given purified F1Ccan be present as a solid that contains, e.g., less than about 15% w/wor less than about 10% w/w or less than about 8% w/w or less than about5% w/w or less than about 3% w/w or less than about 1% w/w of one, twoor more other F1Cs, excipients, synthetic by-products, decompositionproducts or synthesis or purification reactants or reagents. Similarly,the F1C can be present in a solution or suspension that contains atleast about 90% w/w or at least about 95% w/w or at least about 97% w/wof the F1C and one or more excipients and less than about 10% or 8% or5% or 3% w/w or 1% w/w of one, two or more other F1Cs, excipients,synthetic by-products, decomposition products or synthesis orpurification reactants or reagents.

Various groups that F1Cs contain as described herein, e.g., hydroxylgroups or ketones bonded to the steroid nucleus, or substituted alkylgroups, substituted heterocycles, amino acids and peptides, which cancontain one or more reactive moieties such as hydroxyl, oxo, carboxyl,amino or thiol moieties. Intermediates used to make F1Cs may beprotected as is apparent in the art, e.g., using suitable R^(PR)moieties. Noncyclic and cyclic protecting groups and correspondingcleavage reactions are described in “Protective Groups in OrganicChemistry”, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991,ISBN 0-471-62301-6) (hereafter “Greene”) and will not be detailed here.

In the context of the present invention, these protecting groups aregroups that can be removed from a F1C without irreversibly changing thecovalent bond structure or oxidation/reduction state of the remainder ofthe molecule. For example, the protecting group, —R^(PR), that is bondedto an —OR^(PR) or —NHR^(PR) group can be removed to form —OH or —NH₂,respectively, without affecting other covalent bonds in the molecule.Protecting groups for carbonyl or ketone moieties include ethyleneketals, e.g., —O—CH₂—CH₂—O—. At times, when desired, more than oneprotecting group can be removed at a time, or they can be removedsequentially. In F1Cs containing more than one protecting group, theprotecting groups are the same or different.

Protecting groups are removed by known procedures, although it will beunderstood that the protected intermediates fall within the scope ofthis invention. The removal of the protecting group may be arduous orstraightforward, depending upon the economics and nature of theconversions involved. In general, one will use a protecting group withexocyclic amines or with carboxyl groups during synthesis of a F1C. Formost therapeutic applications amine groups should be deprotected.Protecting groups commonly are employed to protect against covalentmodification of a sensitive group in reactions such as alkylation oracylation. Ordinarily, protecting groups are removed by, e.g.hydrolysis, elimination or aminolysis. Thus, simple functionalconsiderations will suffice to guide the selection of a reversible or anirreversible protecting group at a given locus on the F1Cs. Suitableprotecting groups and criteria for their selection are described in T.W. Greene and P. G. M. Wuts, Eds. “Protective Groups in OrganicSynthesis” 2nd edition, Wiley Press, at pps. 10-142, 143-174, 175-223,224-276, 277-308, 309-405 and 406-454.

Characterization of a protecting group is made in the conventionalmanner, e.g., as described by Kocienski, Philip J.; “Protecting Groups”(Georg Thieme Verlag Stuttgart, N.Y., 1994) (hereafter “Kocienski”),Section 1.1, page 2, and Greene Chapter 1, pages 1-9. In particular, agroup is a protecting group if when, based on mole ratio, 90% of thatprotecting group has been removed by a deprotection reaction, no morethan 50%, typically 25%, more typically 10%, of the deprotected productmolecules have undergone changes to their covalent bond structure oroxidation/reduction state other than those occasioned by the removal ofthe protecting group. When multiple protecting groups of the same typeare present in the molecule, the mole ratios are determined when all ofthe groups of that type are removed. When multiple protecting groups ofdifferent types are present in the molecule, each type of protectinggroup is treated (and the mole ratios are determined) independently ortogether with others depending on whether the deprotection reactionconditions pertinent to one type are also pertinent to the other typespresent. In one embodiment, a group is a protecting group if when, basedon mole ratio determined by conventional techniques, 90% of thatprotecting group has been removed by a conventional deprotectionreaction, no more than 50%, typically 25%, more typically 10%, of thedeprotected product molecules have undergone irreversible changes totheir covalent bond structure or oxidation/reduction state other thanthose occasioned by the removal of the protecting group. Irreversiblechanges require chemical reactions (beyond those resulting from aqueoushydrolysis, acid/base neutralization or conventional separation,isolation or purification) to restore the covalent bond structure oroxidation/reduction state of the deprotected F1C.

Protecting groups are also described in detail together with generalconcepts and specific strategies for their use in Kocienski, Philip J.;“Protecting Groups” (Georg Thieme Verlag Stuttgart, N.Y., 1994), whichis incorporated by reference in its entirety herein. In particularChapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2,Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol ProtectingGroups, pages 95-117, Chapter 4, Carboxyl Protecting Groups, pages118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184, Chapter6, Amino Protecting Groups, pages 185-243, Chapter 7, Epilog, pages244-252, and Index, pages 253-260, are incorporated with specificity inthe context of their contents. More particularly, Sections 2.3 SilylEthers, 2.4 Alkyl Ethers, 2.5 Alkoxyalkyl Ethers (Acetals), 2.6 Reviews(hydroxy and thiol protecting groups), 3.2 Acetals, 3.3 SilyleneDerivatives, 3.4 1,1,3,3-Tetraisopropyldisiloxanylidene Derivatives, 3.5Reviews (diol protecting groups), 4.2 Esters, 4.32,6,7-Trioxabicyclo[2.2.2]octanes [OBO] and Other Ortho Esters, 4.4Oxazolines, 4.5 Reviews (carboxyl protecting groups), 5.2 O,O-Acetals,5.3 S,S-Acetals, 5.4 O,S-Acetals, 5.5 Reviews (carbonyl protectinggroups), 6.2 N-Acyl Derivatives, 6.3 N-Sulfonyl Derivatives, 6.4N-Sulfenyl Derivatives, 6.5 N-Alkyl Derivatives, 6.6 N-SilylDerivatives, 6.7 Imine Derivatives, and 6.8 Reviews (amino protectinggroups), are each incorporated with specificity whereprotection/deprotection of the requisite functionalities is discussed.Further still, the tables “Index to the Principal Protecting Groups”appearing on the inside front cover and facing page, “Abbreviations” atpage xiv, and “reagents and Solvents” at page xv are each incorporatedin their entirety herein at this location.

Typical hydroxy protecting groups are described in Greene at pages14-118 and include Ethers (Methyl); Substituted Methyl Ethers(Methoxymethyl, Methylthiomethyl, t-Butylthiomethyl,(Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl,p-Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl,t-Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl,2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl,Bis(2-chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl,Tetrahydropyranyl, 3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl,1-Methoxycyclohexyl, 4-methoxytetrahydropyranyl, 1,4-Dioxan-2-yl,Tetrahydrofuranyl, Tetrahydrothiofuranyl); Substituted Ethyl Ethers(1-Ethoxyethyl, 1-(2-Chloroethoxy)ethyl, 1-Methyl-1-methoxyethyl,1-Methyl-1-benzyloxyethyl, 1-Methyl-1-benzyloxy-2-fluoroethyl,2,2,2-Trichloroethyl, 2-Trimethylsilylethyl, 2-(Phenylselenyl)ethyl,t-Butyl, Allyl, p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl,Benzyl); Substituted Benzyl Ethers (p-Methoxybenzyl,3,4-Dimethoxybenzyl, o-Nitrobenzyl, p-Nitrobenzyl, p-Halobenzyl,2,6-Dichlorobenzyl, p-Cyanobenzyl,p-Phenylbenzyl, 2- and 4-Picolyl,3-Methyl-2-picolyl N-Oxido, Diphenylmethyl, p,p′-Dinitrobenzhydryl,5-Dibenzosuberyl, Triphenylmethyl, 1,3-Benzodithiolan-2-yl,Benzisothiazolyl, S,S-Dioxido); Silyl Ethers (Trimethylsilyl,Triethylsilyl, Triisopropylsilyl, Dimethylisopropylsilyl,Diethylisopropylsily, Dimethylthexylsilyl, t-Butyldimethylsilyl,t-Butyldiphenylsilyl, Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl,Diphenylmethylsilyl, t-Butylmethoxyphenylsilyl); Esters (Formate,Benzoylformate, Acetate, Choroacetate, Dichloroacetate,Trichloroacetate, Trifluoroacetate, Methoxyacetate; Carbonates (Methyl,9-Fluorenylmethyl, Ethyl, 2,2,2-Trichloroethyl, 2-(Trimethylsilyl)ethyl,2-(Phenylsulfonyl)ethyl, 2-(Triphenylphosphonio)ethyl, Isobutyl, Vinyl,Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl, 3,4-Dimethoxybenzyl,o-Nitrobenzyl, p-Nitrobenzyl); Groups With Assisted Cleavage(2-Iodobenzoate, 4-Azidobutyrate, 4-Nitro-4-methyl pentanoate,o-(Dibromomethyl)benzoate, 2-Formylbenzenesulfonate,2-(Methylthiomethoxy)ethyl Carbonate, 4-(Methylthiomethoxy)butyrate,2-(Methylthiomethoxymethyl)benzoate); Other Esters(2,6-Dichloro-4-methylphenoxyacetate,2,6-Dichloro-4-(1,1,3,3-tetramethyl-butyl)phenoxyacetate, Isobutyrate,Monosuccinoate, (E)-2-Methyl-2-butenoate (Tigloate),o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, α-Naphthoate, Nitrate,Alkyl N,N,N′,N′-Tetramethylphosphorodiamidate, N-Phenylcarbamate,Borate, Dimethylphosphinothioyl, 2,4-Dinitro-phenylsulfenate); andSulfonates (Sulfate, Methanesulfonate (Mesylate), Benzylsulfonate,Tosylate (Tos)). More typically hydroxy protecting groups includesubstituted methyl ethers, substituted benzyl ethers, silyl ethers, andesters including sulfonic acid esters, still more typically, esters,trialkylsilyl ethers and tosylates, such as acetates, trimethylsilyl andmethoxymethyl.

Typical 1,2- and 1,3-diol protecting groups are described in Greene atpages 118-142 and include Cyclic Acetals and Ketals (Methylene,Ethylidene, 1-t-Butylethylidene, 1-Phenylethylidene,(4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide(Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene,Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene,3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters(Methoxymethylene, Ethoxymethylene, Dimethoxymethylene,1-Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene,alpha-Methoxybenzylidene, 1-(N,N-Dimethylamino)ethylidene Derivative,alpha-(N,N-Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene);and Silyl Derivatives (Di-t-butylsilylene Group,1,3-(1,1,3,3-Tetraiso-propyldisiloxanylidene) Derivative,Tetra-t-butoxydisiloxane-1,3-diylidene Derivative, Cyclic Carbonates,Cyclic Boronates, Ethyl Boronate, Phenyl Boronate). More typically, 1,2-and 1,3-diol protecting groups include epoxides and acetonides.

Typical amino protecting groups are described in Greene at pages 315-385and include Carbamates (Methyl and Ethyl, 9-Fluorenylmethyl,9(2-Sulfo)fluoroenylmethyl, 9-(2,7-Dibromo)fluorenylmethyl,2,7-Di-t-buthyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]-methyl,4-Methoxy-phenacyl); Substituted Ethyl (2,2,2-Trichoroethyl,2-Trimethylsilylethyl, 2-Phenylethyl, 1-(1-Adamantyl)-1-methylethyl,1,1-Dimethyl-2-haloethyl, 1,1-Dimethyl-2,2-dibromoethyl,1,1-Dimethyl-2,2,2-trichloroethyl, 1-Methyl-1-(4-biphenylyl)ethyl,1-(3,5-Di-t-butylphenyl)-1-methylethyl, 2-(2′- and 4′-Pyridyl)ethyl,2-(N,N-Dicyclohexylcarboxamido)ethyl, t-Butyl, 1-Adamantyl, Vinyl,Allyl, 1-Isopropylallyl, Cinnamyl, 4-Nitrocinnamyl, 8-Quinolyl,N-Hydroxypiperidinyl, Alkyldithio, Benzyl, p-Methoxybenzyl,p-Nitrobenzyl, p-Bromobenzyl, p-Chorobenzyl, 2,4-Dichlorobenzyl,4-Methylsulfinylbenzyl, 9-Anthrylmethyl, Diphenylmethyl); Groups WithAssisted Cleavage (2-Methylthioethyl, 2-Methylsulfonylethyl,2-(p-Toluenesulfonyl)ethyl, [2-(1,3-Dithianyl)]methyl,4-Methylthiophenyl, 2,4-Dimethylthiophenyl, 2-Phosphonioethyl,2-Triphenylphosphonioisopropyl, 1,1-Dimethyl-2-cyanoethyl,m-Choro-p-acyloxybenzyl, p-(Dihydroxyboryl)benzyl,5-Benzisoxazolylmethyl, 2-(Trifluoromethyl)-6-chromonyl methyl);

Groups Capable of Photolytic Cleavage (m-Nitrophenyl,3,5-Dimethoxybenzyl, o-Nitrobenzyl, 3,4-Dimethoxy-6-nitrobenzyl, Phenyl(o-nitrophenyl)methyl); Urea-Type Derivatives(Phenothiazinyl-(10)-carbonyl Derivative,N′-p-Toluenesulfonylaminocarbonyl, N′-Phenylaminothiocarbonyl); OtherCarbamates (t-Amyl, S-Benzyl Thiocarbamate, p-Cyanobenzyl, Cyclobutyl,Cyclohexyl, Cyclopentyl, Cyclopropylmethyl, p-Decyloxybenzyl,Diisopropylmethyl, 2,2-Dimethoxycarbonylvinyl,o-(N,N-Dimethyl-carboxamido)benzyl,1,1-Dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-Dimethylpropynyl,Di(2-pyridyl)methyl, 2-Furanylmethyl, 2-Iodoethyl, Isobutyl,Isonicotinyl. More typically, amino protecting groups include carbamatesand amides, still more typically, N-acetyl groups.

Groups capable of biological cleavage typically include prodrugs. Someexemplary groups are described in “Design of Prodrugs”, Hans Bundgaard(Elsevier, N.Y., 1985, ISBN 0-444-80675-X) (Bundgaard) and will not bedetailed here. In particular, Bundgaard, at pages 1-92, describesprodrugs and their biological cleavage reactions for a number offunctional group types. Prodrugs for carboxyl and hydroxyl groups aredetailed in Bundgaard at pages 3 to 10, for amides, imides and otherNH-acidic compounds at pages 10 to 27, amines at pages 27 to 43, andcyclic prodrugs at pages 62 to 70. These moieties are optionally bondedto the steroid at one, two or more of the variable groups that arebonded to the rings in the F1Cs, e.g., one or more R¹-R⁶, R¹⁰, R¹⁵, R¹⁷and R¹⁸.

In some embodiments one or more F1Cs or groups of F1Cs may be excludedfrom one or more of the uses disclosed herein. For example, if thesubject has or is susceptible to developing a memory impairingneurological disorder or memory impairment condition, excluded compoundscan include 5-androstene-3β-ol-7, 17-dione or5-androstene-3β,7-diol-17-one or a derivative of these compounds thatcan has a group at the 7-position that can convert to —OH or ═O byhydrolysis. In other cases, the F1Cs can exclude one or more of4-pregnene-11β, 17α,21-triol-3,20-dione,17α,21-dihydroxypregn-4-ene-3,11,20-trione,11β,21-dihydroxy-3,20-dioxopregn-4-en-18-al, 11β,17α,21-trihydroxypregna-1,4-diene-3,20-dione,17α,21-dihydroxypregna-1,4-diene-3,11,20-trione,3β-hydroxypregn-5-ene-20-one, 3β-hydroxyandrost-5-ene-17-one,pregn-4-ene-3,20-dione, 21-hydroxypregn-4-ene-3,20-dione, 9-fluoro-11β,16α,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione, 9-fluoro-11β,16α, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione, 9-fluoro-11β,17α,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione,dehydroepiandrosterone-3-sulfate,1,4-pregnadiene-17α,21-diol-3,11,20-trione, androsterone, androsteroneacetate, androsterone propionate, androsterone benzoate,androst-5-ene-3β, 17β-diol, androst-5-ene-3β, 17β-diol-3-acetate,androst-5-ene-3β, 17β-diol-17-acetate, androst-5-ene-3β, 17β-diol-3β,17-diacetate, androst-5-ene-3β, 17β-diol-17-benzoate, androst-5-ene-3β,17β-diol-3-acetate-17-benzoate, androst-4-ene-3β, 17-dione,androst-5-ene-3β,7β, 17β-triol, androst-5-ene-3β,7α, 17β-triol,dehydroepiandrosterone, 4-dihydrotestosterone, 5α-dihydrotestosterone,dromostanolone, dromostanolone propionate, ethylestrenol, nandrolonephenpropionate, nandrolone decanoate, nandrolone furylpropionate,nandrolone cyclohexanepropionate, nandrolone benzoate, nandrolonecyclohexanecarboxylate, oxandrolone, stanozolol, testosterone, methyltestosterone, testolactone, oxymetholone, fluoxymesterone,acetoxypregnenolone, allylestrenol, anagestone acetate, chlormadinoneacetate, cyproterone, cyproterone acetate, desogestrel,dihydrogesterone, dimethisterone, ethisterone (17α-ethynyltestosterone),ethynodiol diacetate, fluorogestone acetate, gestadene,hydroxyprogesterone, hydroxyprogesterone acetate, hydroxyprogesteronecaproate, 3-ketodesogestrel, hydroxymethylprogesterone,hydroxymethylprogesterone acetate, levonorgestrel, lynestrenol,medrogestone, medroxyprogesterone acetate, megestrol, megestrol acetate,melengestrol acetate, norethindrone, norethindrone acetate,norethisterone, norethisterone acetate, norethynodrel, norgestimate,norgestrel, norgestrienone, normethisterone, and progesterone,progesterone, cyproterone acetate, norethindrone, norethindrone acetate,levonorgestrel, an ester of any of the foregoing compounds (e.g.,acetate, enanthate, propionate, isopropionate, cyclopropionate,isobutyrate, butyrate, valerate, caproate, isocaproate, hexanoate,heptanoate, octanoate, nonanoate, decanoate, undecanoate, phenylacetateor benzoate esters, e.g., hydroxyl esters), a naturally occurringglucorcorticoid, a species disclosed herein or a derivative of any ofthese that can convert to these molecules by hydrolysis or metabolism,e.g., a metabolizable or hydrolyzable ester or ether such as a cyclicketal, an acetate, a diacetete, a proprionate, a diproprionate, or anO-alkyl, an acyl, e.g., —C(O)—C1-C6 alkyl or another moiety that isbonded at, e.g., a variable group such as for R¹-R⁶.

Dosages of F1C and dosing protocols or methods. In treating any of theconditions or symptoms disclosed herein, one can continuously orintermittently administer the F1C(s) to a subject having or susceptibleto developing the condition or symptom. In treating a condition such asan infection, a hyperproliferation condition, an inflammation conditionor another condition disclosed herein with a F1C using an intermittentdosing can avoid or ameliorate some of the undesired aspects normallyassociated with discontinuous dosing. Such undesired aspects includedevelopment of resistance of a pathogen such as a pathogen disclosedherein, e.g., a virus or bacterium such as HIV or Staphylococcus aureusor a parasite such as a Plasmodium parasite, to the therapeutic agent,failure of the patient or subject to adhere to a daily dosing regimen orreduction of the dosages of other therapeutic agents and/or theirassociated unwanted side effects or toxicities, e.g., reduction or atoxic effect of a chemotherapy or radiation exposure. In any of thecontinuous or intermittent dosing protocols described herein, otherappropriate treatments can be applied as the subject's clinicalsituation dictates. Suitable other appropriate treatments or therapeuticagents are described elsewhere herein and in the cited references.

In any of the continuous or in any step(s) in the intermittent dosingprotocols described herein, or in treating any of the diseases,conditions or symptoms described herein, the F1C(s) can be administeredby one or more suitable routes, e.g., oral, buccal, sublingual,intramuscular (i.m.), subcutaneous (s.c.), intravenous (i.v.),intradermal, another parenteral route or by an aerosol. The effectivedaily dose in such methods will typically comprise about 0.05 mg/kg/dayto about 200 mg/kg/day, about 0.1 to about 100 mg/kg/day, about 6-45mg/kg/day, about 1-6 mg/kg/day, including about 0.2 mg/kg/day, 0.5mg/kg/day, about 1 mg/kg/day, about 2 mg/kg/day, about 4 mg/kg/day,about 6 mg/kg/day, about 10 mg/kg/day, about 20 mg/kg/day, about 40mg/kg/day or about 100 mg/kg/day. Higher dosages, e.g., about 250mg/kg/day, about 300 mg/kg/day or about 350 mg/kg/day can also beutilized, e.g., in veterinary applications. One can administer theF1C(s) orally using about 4 to about 60 mg/kg/day, usually about 6-30mg/kg/day. In some embodiments, the intermittent dosing methods excludedosing protocols that are commonly used to deliver contraceptivesteroids to, e.g., human females, such as daily dosing for 21 days,followed by no dosing for 7 days. For humans, dosing is generally about0.005 mg/kg/day to about 30 mg/kg/day, typically about 0.5-5 mg/kg/day.Low dosages for humans such as about 0.005 mg/kg/day to about 0.2mg/kg/day or about 0.25-10 mg/day, can be used with, e.g., local,topical, transmucosal or intravenous administration and higher dosagessuch as about 0.1 mg/kg/day to about 20 mg/kg/day or about 5-200 mg/day,can be used, e.g., for oral, subcutaneous or other systemic or localadministration route. For non-human subjects, e.g., mammals such asrodents or primates, the effective daily dosage may comprise about 0.05mg/kg/day to about 350 mg/kg/day. F1C formulation dosages or daily dosesor unit doses or subdoses for subjects such as humans and mammalsinclude, e.g., about 1, 5, 10, 15, 20, 25, 50, 75, 100, 125, 15β, 175,200, 225, 250, 275, 300, 325, 350, 400 or 450 mg of the F1C.

An effective dosage or an effective amount of a F1C(s) is one that issufficient to result in, e.g., a detectable change in a symptom or animmune parameter such as one described herein. An effective dosage (ordaily dosage) may be administered to a subject over a period of time,e.g., at least about 1-14 days before a symptom change or an immuneparameter detectably changes. Effective amounts of a F1C can bedelivered using the dosages and dosing protocols described herein.

In some embodiments, F1C are used to treat, ameliorate, prevent or slowthe progression of a condition or disease described herein by continuousdaily dosing of the F1C for 1 day to 1, 2, 3 years or more. In relatedembodiments, F1C are used to treat, ameliorate, prevent or slow theprogression of a condition or disease described herein by continuousdosing the F1C every other day or dosing every third, fourth, fifth,sixth, seventh or 14^(th) day over a time period of 3 days to 1, 2, 3years or more, e.g., dosing for about 2, 3, 4, 5, 6 or 7 days or about1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 or more weeks. Daily doses in anyof these dosing regimens or protocols may be subdivided into 2 or 3subdoses.

Intermittent dosing protocols include administration of a F1C, e.g.,orally, topically or parenterally as follows: (1) daily dosing or dosingevery other day or dosing every third day or dosing every fourth day ordosing every fifth day or dosing every seventh day for about 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 28 days toabout 190 days or more, e.g., 1 or 2 years, (2) no dosing of the F1C for1 to about 190 consecutive days (e.g., about 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 days to about 20 days), (3) daily dosing for about 3 to about190 days (e.g., about 3 to about 20 days), and (4) optionally repeatingstep (2) or a variation of step (2) and (5) optionally repeating thesteps (1), (2), (3) and (4) 1, 2, 3, 4, 5, 6, 10, 15, 20, 30 or moretimes. In some embodiments, the dosing of steps (1) and (3) are thesame, while in others, step (1) dosing is for a longer time than step(3). Less frequently, step (1) dosing will be for a shorter time. Insome embodiments, steps (1)-(4) or (1)-(5) of the dosing protocoldescribed above where step (4) is included, is repeated at least onetime, e.g., at least 2, 3, 4, 5 or 6 times. For conditions that tend toremain chronic, e.g., HIV infection or other chronic conditionsdescribed herein, any of these intermittent dosing protocols can bemaintained over a relatively long time period, e.g., for at least about4 months or 6 months to about 5 or more years.

In some embodiments, the number of days of dosing in steps (1) and (3)is the same in each round of treatment, i.e., each time period in step(1) and (3) is the same in the initial and subsequent rounds of themethod. In other embodiments they differ. Thus, in some embodiments,step (1) may comprise dosing of about 1 mg/day to about 1500 mg/day of aF1C for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more consecutive days. Then,step (2) may comprise not administering any F1C for at least about 2, 3,4, 5, 6, 7, 14, 21, 28, 42, 56, 84, 98, 112 or more consecutive days.Step (3) could comprise dosing of a F1C for 1, 2, 3, 4, 5, 6, 7, 8, 9,10 or more consecutive days. When step (4) is included it is typicallyabout 1 day to about 3 months, usually 3 days to about 6 weeks. On dayswhen the F1C is administered to the subject, it may be delivered in asingle dose or in two, three or more subdoses at, e.g., about 12 hour orabout 8 hour time intervals.

Exemplary embodiments comprise (1) administering a F1C(s) once every (asa single dose or as 2 or 3 daily subdoses) 2 days, every 3 days or every4 days or once per week for about 3, 5, 7, 9, 11, 13, 14, 15, 21, 28 ormore days, followed by (2) no dosing for about 2, 3, 4, 5, 6, 10, 14,15, 21, 20, 25, 28, 30, 35, 40, 42, 45, 49, 56, 60, 70, 77, 84, 98, 112or more days and then (3) administering the F1C(s) at least once more onone day, e.g., administering the F1C(s) as described in step (1), (4)not dosing for 2, 3, 4, 5, 7 or more days, e.g., as described in step(2) for 1, 2, 3, 4, 5, 6, 7 or 8 weeks, and (5) optionally repeatingsteps (1), (2), (3) and (4) 1, 2, 3, 4, 5 or 6 times or more. Any of thedosing protocols described herein may be coincident or essentiallycoincident with the appearance or expected appearance of a clinicalcondition, e.g., dosing with a F1C may commence at about 1, 2 or 3 hoursafter to about 1, 2, 3, 4 or 5 days after exposure of a subject toradiation or a chemotherapy such as a cancer chemotherapy, to prevent ortreat, e.g., reduce the length and/or severity of an acute or chronicside-effect such as neutropenia, such as grade 3 or grade 4 neutropenia,thrombocytopenia, lung fibrosis or inflammation that can be associatedwith the radiation exposure or the chemotherapy.

Other embodiments comprise (1) administering a F1C(s) once every day (asa single dose or as 2 or 3 daily subdoses) for 3-15 or about 8-12 days,followed by (2) no dosing for 1, 2, 3, 4, 5, 6, 10, 15, 20, 25, 30, 35,40, 45, 50, 56, 70, 84, 98, 112 or more days and then (3) administeringthe F1C(s) at least once more on one day, e.g., administering the F1C(s)once per day for about 3-15 or about 8-12 consecutive days essentiallyas described in step (1) and (4) optionally repeating steps (1), (2) and(3) 1, 2, 3, 4, 5 or 6 times or more. In a subset of these embodiments(1) comprises administering a F1C(s) once every day for about 5, 6, 7,8, 9 or 10 days, followed by (2) no dosing for about 10-40 days, (3)administering the F1C(s) at least once more on one day, e.g.,administering the F1C(s) once per day for about 10 days (4) repeatingstep (2) or a variation, e.g., no dosing for about 5-45 days, and (5)optionally repeating steps (1), (2), (3) and (4) or a variation thereofthose steps 1, 2, 3, 4, 5 or 6 times or more, (5) administering by s.c.or i.m. injection of about 5-45 mg/kg/dose, about 6-43 mg/kg/dose orabout 7-43 mg/kg/dose of a group 3 compound such as compound 1.1.5.9 ingroup 3 described below, once each 1, 2, 3, 4, 5, 6, 7, 8 or 10 daysover a period of about 15-28 days, optionally beginning at about 1-72hours after, about 1-48 hours after, about 1-24 hours after or about24-72 hours after exposure of the subject to radiation or a cytotoxicchemotherapy, (6) administering orally or by s.c. or i.m. injectionabout 0.5-10 mg/kg/dose, e.g., about 1.5-3 mg/kg/dose of a group 3compound such as compound 1.1.5.1 described below, once each 1, 2, 3, 4,5, 6, 7 or 8 days over a period of about 15-30 days, e.g., over a periodof 12, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26 or 32 days,optionally beginning at about 1-72 hours after, about 1-48 hours after,about 1-24 hours after or about 24-72 hours after exposure of thesubject to radiation or a cytotoxic chemotherapy.

Any of the dosing protocols described herein may be repeated to coincideor essentially coincide as described above or elsewhere herein withcycles of a chemotherapy or radiation exposure, or with the appearanceof symptoms of a clinical condition or disease, e.g., fever, fatigue orpain. Thus periods of 1 week or 2 weeks or 4 weeks to several months,e.g., 2, 3, 4, 5, 6, 7, 8 or more months to about 24 months or about 36months or more may separate cycles of continuous or intermittent dosingwith a F1C. Any given dosing protocol may be selected to provideselected levels of the F1C in serum, blood or tissue for selected timeperiods. Thus, a dosing protocol may be selected to attain a blood,serum or tissue level of a F1C that is about 0.5 nM to about 4000 nM,e.g., about 1-1000 nm, about 10-800 nm or about 30-650 nM (about 1-800ng/mL or 10-250 ng/mL in blood or serum), for at least about 1-24 hoursper day, e.g., for about 1-2 hours, about 2-8 hours or about 2-12 hoursper day, during an entire dosing period or most of a dosing period,e.g., beginning at about 1, 2, 3 or 4 days into a continuous (daily) orintermittent dosing protocol, and/or on days when dosing occurs and/orfor several days after to about 1, 2, 3, 4, 5, 6, 7 or 8 weeks after adosing protocol has ended.

One aspect of the continuous and intermittent dosing protocols ismonitoring the subject's response to a particular dosing regimen orschedule, e.g., to any intermittent administration method disclosedherein. For example, while dosing a subject who has a viral infection(e.g., HCV, HIV, SIV, SHIV), one can measure the subject's or pathogen'sresponse, e.g., amelioration of one or more symptoms or a change ininfectious particles or viral DNA or RNA in the serum or a change in animmune parameter of interest. Once a response is observed dosing can becontinued for one, two or three additional days, followed bydiscontinuing the dosing for at least one day (at least 24 hours),usually for at least about 2, 3, 4, 5, 6, 7, 14, 21, 28, 42, 56, 70, 84,98, 112 or more days. Once the subject's response shows signs ofremission (e.g., a symptom begins to intensify, viral serum DNA or RNAbegins to increase or an immune parameter, e.g., as described herein,begins to deteriorate), dosing can be resumed for another course. Anaspect of the subject's response to F1C(s) is that the subject may showa measurable response within a short time, usually about 5-10 days,which allows straightforward tracking of the subject's response, e.g.,by monitoring viral titer in peripheral white blood cells (“PBMC”), bymeasuring viral nucleic acid levels in the blood or by measuring a whiteblood cell population(s) or expression of a cytokine or interleukin bye.g., white blood cells or a subset(s) thereof. One may monitor one ormore immune cell subsets, e.g., NK, LAK, dendritic cells or cells thatmediate ADCC immune responses, during and after intermittent dosing tomonitor the subject's response and to determine when furtheradministration of the F1C is indicated. These cell subsets are monitoredas described herein, e.g., by flow cytometry.

For any of the treatments or methods described herein, prolongedbeneficial effects or a sustained immune response by a subject mayresult from a single administration or short course, e.g, about 1-5 daysor about 8 days to about 4 months, of continuous or intermittentadministration of a F1C. A single administration means that a F1C isadministered to the subject in one, two, three or more doses within a 24hour period and no further administration of any F1C to the subjectoccurs for at least about 4-90 days, e.g., about for at least about 30days to about 2 months, or for about 1.5, 2, 3, 4, 5, 6 or more months.Prolonged beneficial effects or immune responses may also persist aftera short course of treatment has been completed (e.g., daily dosing for2, 3, 4, 5 or 6 days) and the subject is no longer receiving any F1C,or, in some cases, any other therapeutic treatment to treat the primarycause of the subject's pathological condition. Such beneficial effectscan persist for more than about 5-30 days, e.g., for at least about 21,28, 42, 56, 70, 84, 98, 112 or more days. Thus, administration of a F1Cprovides a method to help protect a subject against progression of aninfection or against adverse consequences of unwanted immune reactions,e.g., inflammation or immunosuppression or as disclosed herein, withoutany dosing of the compound for at least 1, 2 or 3 months after aninitial dosing protocol.

Other intermittent dosing embodiments comprise administering to asubject having or susceptible to a condition as described herein aneffective amount of a F1C using an initial induction or high dosingregimen. The high dosing regimen may comprise, e.g., 1, 2, 3, 4, 5, 6, 7or more daily doses of about 4 to about 40 mg/kg that are administereddaily, every other day, every 3^(rd) day, every 4^(th) day or every5^(th) day. Then, the subject is not dosed with a F1C for a period,e.g., of about 5, 7, 14, 21, 28, 42, 56, 70, 84, 98, 112 or moreconsecutive days. Then a lower daily dosing regimen is administered tothe subject, e.g., about 0.2 mg/kg to about 4 or about 6 mg/kg,essentially as described for the high dosing regimen. Alternatively,this low dosing regimen may comprise 1, 2, 3, 6 or more rounds of a lowto moderate initial level, e.g., about 2 to about 10 mg/kg/day,optionally followed by subsequent rounds of daily dosing that decreasethe initial low to moderate level by about 10%, 20%, 30%, 40% or more ineach subsequent round of treatment, which is continued untiladministration is discontinued. These embodiments can be used with anyof the dosing protocols described herein.

Dosages of the F1C, continuous or intermittent dose protocols, routes ofadministration and the use of combination therapies with other standardtherapeutic agents or treatments could be applied essentially asdescribed above for any of the diseases or conditions that are disclosedherein. Thus, the F1Cs may be administered prophylactically ortherapeutically in chronic or acute conditions. In acute conditions, theF1Cs may also be administered at the time of occurrence or relativelysoon after an acute event such as the onset of surgery, a migraine orthe occurrence of trauma, e.g., a central nervous system injury, acerebral stroke or myocardial infarction. For acute events, a F1C maythus be administered concurrently, e.g., within about 15 minutes orabout 30 minutes or about 45 minutes of the onset or occurrence of theacute event, or at a later time, e.g., at about 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24, 26, 28, 30, 36, 42, 48,54, 60, 72, 84, 96, 108 or 120 hours after the onset or occurrence ofthe acute event or at any range of times defined by any two of theselater times. The F1Cs may thus be administered at about 4-120 hours,about 6-120 hours, about 8-48 hours, 8-24 hours, 8-12 hours, 10-12hours, 10-14 hours, 10-16 hours, about 10-24 hours, 12-14 hours or about12-16 hours after an acute event starts, occurs or is believed to havebegun, e.g., after a surgical procedure has been completed or after aradiation treatment has ended or after a cytotoxic chemotherapy or amyelosuppressive cancer chemotherapy has been administered to thesubject.

Alternatively, the F1Cs may be administered before, e.g., within about15 minutes, about 30 minutes or about 45 minutes before the onset oroccurrence of a planned or anticipated acute event, or at an earliertime, e.g., at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 18, 20, 22, 24, 26, 28, 30, 36, 42, 48, 54, 60, 72, 84, 96, 108 or120 hours before the onset or occurrence of the acute event. The F1Csmay thus be administered at about 6-120 hours, about 8-48 hours, about10-24 hours, about 10-16, or about 12-16 hours before the planned oranticipated acute event, e.g., before a planned surgery or a radiationtreatment starts or occurs.

Formulations and compositions for preparing formulations. Inventionembodiments include formulations described here and elsewhere in thisdisclosure. While it is possible for the F1C(s) to be administered to asubject or incubated with a subject's cells in vitro as the compoundalone, it is usual to use F1C in a formulation or at least in acomposition that contains 1, 2, 3, 4, 5, 6 or more excipients. Theformulations, which are useful for veterinary or human pharmaceuticaluse, comprise at least one F1C, together with 1, 2, 3, 4, 5, 6 or moreexcipients and optionally one or more additional therapeuticingredients.

The invention includes compositions comprising one or morepharmaceutically acceptable excipients or carriers. The compositions areused to prepare formulations suitable for human or animal use.Formulations may be designed or intended for oral, rectal, nasal,topical or transmucosal (including buccal, sublingual, ocular, vaginaland rectal) and parenteral (including subcutaneous, intramuscular,intravenous, intradermal, intrathecal, intraocular and epidural)administration. In general, aqueous and non-aqueous liquid or creamformulations are delivered by a parenteral, oral or topical route. Inother embodiments, the F1C(s) may be present as an aqueous or anon-aqueous liquid formulation or a solid formulation suitable foradministration by any route, e.g., oral, topical, buccal, sublingual,parenteral, aerosol, a depot such as a subcutaneous depot or anintraperitoneal or intramuscular depot or a rectal or vaginalsuppository. The preferred route may vary with, for example, thesubject's pathological condition or weight or the subject's response totherapy with a F1C or other therapy that is used or that is appropriateto the circumstances. The F1C formulations can also be administered bytwo or more routes, e.g., subcutaneous injection and buccal orsublingual, where these delivery methods are essentially simultaneous orthey may be essentially sequential with little or no temporal overlap inthe times at which the compound is administered to the subject.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods known in the art ofpharmacy. Techniques, excipients and dosage forms are found in, e.g.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1985, 17^(th) edition; Nema et al., PDA J. Pharm. Sci. Tech. 199751:166-171; Pharmaceutical Coating Technology, 1995, G. Cole, et al.,editors, Taylor & Francis, ISBN 0 136628915; Pharmaceutical DosageForms, 1992 2^(nd) revised edition, volumes 1 and 2, H. A. Lieberman, etal., editors, Marcel Dekker, ISBN 0824793870; PharmaceuticalPreformulation, 1998, pages 1-306, J. T. Carstensen, TechnomicPublishing Co. ISBN 1566766907; and Encyclopedia of PharmaceuticalTechnology, volumes 1, 2 and 3, 2^(nd) edition, 2002, J. Swarbrick andJ. C Boylan, editors, Marcel Dekker, Inc., New York, N.Y.

Methods to make invention formulations include the step of bringing intoassociation or contacting a F1C(s) with one or more excipient, such asone described herein or in the cited references. In general theformulations are prepared by uniformly and intimately bringing intoassociation the F1C(s) with liquid excipients or finely divided solidexcipients or both, and then, if appropriate, shaping the product.

Formulations suitable for oral administration are prepared as discreteunits such as capsules, soft gelatin capsules (softgels), cachets,tablets or caplets each containing a predetermined amount of the F1C(s).F1C formulations can also be present as a powder or granules or as asolution or a suspension, colloid or gel in an aqueous liquid or base orin a non-aqueous liquid or base; or as an oil-in-water liquid emulsionor a water-in-oil liquid emulsion. The F1C formulations may also be abolus, electuary or paste. Suspension formulations will typicallycontain about 0.5% w/w or about 1% w/w to about 5%, 10%, 15% or 20% w/wof the F1C, which can be for parenteral use or for other routes ofadministration, e.g., oral softgels.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the F1C(s) in a free-flowing form such as a powderor granules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered orgranulated F1C and one or more excipients, which are optionallymoistened, with an inert liquid diluent or excipient. The tablets mayoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the F1C(s) therefrom. An exemplarytablet or caplet formulation suitable for buccal or sublingual deliveryof a F1C to a subject's tissues comprises about 25 or 50 mg of a F1Ccomprising per 25 mg of the F1C about 6.2 mg povidone, about 0.62 mgmagnesium stearate, about 45 mg mannitol and about 48 mg of compressiblesucrose.

For infections of the eye or other external tissues e.g., the mouth orskin, the formulations are typically applied as a topical ointment orcream containing the F1C(s) in an amount of, for example, about 0.075 toabout 20% w/w (including F1C(s) in a range between about 0.1% and 20% inincrements of 0.1% w/w such as about 0.6% w/w, about 0.7% w/w, about 1%w/w, about 1.5% w/w, about 2% w/w, about 2.5 w/w, about 3% w/w, about 5%w/w, about 7% w/w, about 10% w/w etc.), including about 0.2 to 15% w/wand about 0.5 to 10% w/w. When formulated in an ointment, the F1C(s) maybe employed with either a paraffinic or a water-miscible ointment base.Alternatively, they may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, butane 1,4-diol, mannitol, sorbitol, glycerol and apolyethylene glycol (including, e.g., PEG 300 and PEG 400) and mixturesthereof. The topical formulations may include a compound that enhancesabsorption or penetration of the F1C(s) through the skin or otheraffected areas. Examples of such dermal penetration enhancers includedimethyl sulphoxide and related analogs.

The oily phase of the emulsion formulations may be constituted fromknown excipients in a known manner. While the phase may comprise anemulsifier or emulgent, it typically comprises a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil. Ahydrophilic emulsifier may be included together with a lipophilicemulsifier, which acts as a stabilizer. Some embodiments include both anoil and a fat. Together, the emulsifier(s) with or without stabilizer(s)make up the so-called emulsifying wax, and the wax together with the oiland fat make up the so-called emulsifying ointment base which forms theoily dispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationsinclude Tween60™, Span80™, cetostearyl alcohol, benzyl alcohol, myristylalcohol, glyceryl mono-stearate and sodium lauryl sulfate. Otherexcipients include emulsifying wax, propyl gallate, citric acid, lacticacid, polysorbate 80, sodium chloride, isopropyl palmitate, glycerin andwhite petrolatum.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. Creams are generally anon-greasy, non-staining and washable products with suitable consistencyto avoid leakage from tubes or other containers. Straight or branchedchain, mono- or dibasic alkyl esters such as di-isoadipate, isocetylstearate, propylene glycol diester of coconut fatty acids, isopropylmyristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used. These may be used alone or in combinationdepending on the properties required. Alternatively, high melting pointlipids such as white soft paraffin and/or liquid paraffin or othermineral oils are used.

Formulations suitable for topical administration to the eye include eyedrops, which are usually sterile, wherein the F1C(s) is dissolved orsuspended in a suitable excipient(s), including an aqueous solvent for aF1C(s) that comprise at least about 0.5, one, two or more charges at pHvalues near neutrality, e.g., about pH 6-8. The F1C(s) is typicallypresent in such formulations in a concentration of about 0.5-20% w/w,about 1-10% w/w or about 2-5% w/w.

Formulations suitable for topical administration to oral mucosa includelozenges or tablets comprising the F1C(s) in a flavored basis or amonosaccharide or disaccharide such as sucrose, lactose or glucose andacacia or tragacanth; pastilles comprising the F1C(s) in an inert basissuch as gelatin and glycerin, or sucrose and acacia; and mouthwashescomprising the F1C(s) in a suitable liquid excipient(s). In someembodiments, the lozenges or tablets optionally comprise the property ofrapid dissolution or disintegration, e.g., disintegration within about15 seconds to about 2 minutes, while in others, the lozenges or tabletscomprise the property of slower dissolution or disintegration, e.g.,disintegration within about 2 minutes to about 10 minutes or more.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the F1C(s) such excipients as are known in theart to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats, salts (e.g., NaCl, potassium or sodium carbonateor bicarbonate or potassium or sodium phosphates) and solutes whichrender the formulation isotonic with the blood of the intended subject;and aqueous and non-aqueous sterile suspensions which may includesuspending agents or thickening agents. In general, the F1C that ispresent in liquid compositions or formulations is completely dissolvedin aqueous or non-aqueous excipients. However, in some embodiments,e.g., transient compositions or some formulations, the F1C is partiallydissolved while the remaining portion is present as a solid, which canbe a suspension or a colloid.

Formulations suitable for parenteral delivery of F1Cs to subjects suchas humans or animals typically comprise 1, 2, 3, 4, 5, 6 or moreexcipients. Exemplary embodiments include (1) any two, three or four ofpropylene glycol, PEG200, PEG300, ethanol, benzyl alcohol and benzylbenzoate and (2) any two, three or four of propylene glycol, PEG100,PEG200, PEG300, PEG400, benzyl alcohol and benzyl benzoate. Typicallysuch formulations will contain both propylene glycol and one or morePEGs, e.g., PEG100, PEG200, PEG300 or PEG400, which enhance thesolubility of the F1C by a cosolvent effect.

Formulations, or compositions disclosed herein for use to makeformulations suitable for administration by the routes disclosed hereinoptionally comprise an average particle size in the range of about 0.01to about 500 microns, about 0.1 to about 100 microns or about 0.5 toabout 75 microns. Average particle sizes include a range between 0.01and 500 microns in 0.05 micron or in 0.1 micron or other increments,e.g., an average particle size of about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5,0.7, 1, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6, 7, 8, 9, 10, 15,20, 25, 30, 35, 40, 50, 60, 75, 85, 100, 120, 150, etc. microns). TheF1C itself that is used to make a formulation can have one, two or moreof these average particle sizes. When F1Cs or compositions that comprisea F1C are used as intermediates to make a formulation, they may compriseone, two, three or more of these average particle sizes, or size ranges.In preparing any of the compositions or formulations that are disclosedherein and that comprise a F1C (and optionally one or more excipients),one may optionally mill, sieve or otherwise granulate the compound orcomposition to obtain a desired particle size, e.g., as described above.

Milling or micronization by any other method may occur before or afterthe F1C is contacted with one or more excipients. For example, one maymill a F1C to obtain an average particle size (or diameter) of about0.05-50 μM or about 0.5-10 μM (e.g., about 0.02, 0.04, 0.05, 0.07, 0.1,0.5, 1, 1.5, 2, 2.5, 5, 10, 15, 20, 30, 40, 50, 60, 80, 100 or 120 μMaverage particle size or diameter) before contacting the milled F1C witha liquid or solid excipient. In some cases the F1C is milled or sievedto obtain an average particle size of about 5 μm or about 10 μm beforeit is contacted with a solid or liquid excipient(s) to obtain a solutionor suspension or a powder suitable for making a tablet, capsule or otherdosage form as described herein or in the cited references. Micronizedcompound may be prepared using any suitable process for obtaining smallparticles, e.g., controlled precipitation from a solution, micronizingor milling, a number of which are known in the art. The micronizedparticles may include a percentage of particles that are less than orequal to about 0.1-20 μm in diameter. Ranges of average particle sizesinclude F1Cs of about 0.04-0.6 μm, about 0.04-1.0 μm, about 0.05-0.6 μm,about 0.05-1.0 μm, about 0.1-0.4 μm, about 0.5-1 μm, about 1-20 μm orabout 2-50 μm.

As used herein, reference to an average particle size or an averageparticle diameter means that the material, e.g., a F1C(s), anexcipient(s) or a composition that comprises both, is ground, milled,sieved or otherwise treated so as to comprise the specified averagesize. It is to be understood that some particles may be larger orsmaller, but the composition or the F1C(s) will comprise a significantproportion of the material with the specified size or within anacceptable range of the specified size, e.g., at least about 70% orabout 80% of the particles within about 30% to about 50% of the averagesize or diameter. Micronization methods include milling by ball mills,pin mills, jet mills (e.g., fluid energy jet mills) and grinding,sieving and precipitation of a compound(s) from a solution, see, e.g.,U.S. Pat. Nos. 4,919,341, 5,202,129, 5,271,944, 5,424,077 and 5455049.Average particle size is determined by known methods, e.g., transmissionelectron microscopy, scanning electron microscopy, light microscopy,X-ray diffractometry, light scattering methods or Coulter counteranalysis.

Thus, the F1Cs may comprise a powder that consists of one, two or moreof these average particle sizes and the powder may be contacted with asolid excipient(s), suitably mixed and optionally compressed or formedinto a desired shape. Alternatively, such a F1C(s) is contacted with aliquid excipient(s) to prepare a liquid formulation or a liquidcomposition that is incorporated into a solid formulation. Suitablemicronized formulations thus include aqueous or oily solutions orsuspensions of the F1C(s).

Formulations suitable for aerosol administration typically will comprisea fine powder, e.g., having an average particle size of about 0.1 toabout 20 microns or any one, two or more of the average particle sizeswithin this range that are described above. The powder is typicallydelivered by rapid inhalation through the nasal passage or by inhalationthrough the mouth so as to reach the bronchioles or alveolar sacs of thelungs.

Formulations suitable for aerosol, dry powder or tablet administrationmay be prepared according to conventional methods and may be deliveredwith other therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis of viral or other infections as describedherein. Such formulations may be administered, e.g., orally,parenterally (e.g., intravenous, intramuscular, subcutaneous,intradermal, intrathecal), topically, sublingually or by a buccal orsublingual route.

Micronized F1C is useful, e.g., to facilitate mixing, dissolution oruniform suspension of the F1C in one or more liquid or solid excipients,e.g., a PEG such as PEG 300 or PEG 400, propylene glycol, benzylbenzoate, a complexing agent, such as a cyclodextrin (e.g., an α-, β- orγ-cyclodextrin such as hydroxypropyl-β-cyclodextrin). Micronized F1C isalso useful to facilitate uniformly distributing drug substance when themicronized compound is contacted with one or more solid excipients(e.g., a filler, a binder, a disintegrant, complexing agent (e.g., acyclodextrin such as hydroxypropyl-β-cyclodextrin), a preservative, abuffer or a lubricant).

In related embodiments, suitable compositions or formulations comprise aF1C that is present in two or more physical forms. For example, a liquidcomposition or formulation may comprise a F1C that is present insolution and as undissolved particles, which may be milled as describedherein. Alternatively, a solid composition or formulation may comprise aF1C that is present as an amorphous form and as a crystal or in anencapsulated granule. Such encapsulated granules may comprise a slowrelease type formulation and the F1C that is present may be in one ormore physical forms, e.g., liquids or solids as described herein, butusually as a solid in tablets or other solid formulations.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid excipient, for example water for injection, immediatelyprior to use. In general, solid, liquid or other formulations orcompositions that comprise a F1C, e.g., unit dosages for solid or liquidformulations, are stored in a sealed container, which may optionally beopaque or nearly opaque (e.g., amber or blue glass or brown plastic) toreduce the amount of light that reaches the formulation or composition.Such containers are also optionally sealed, e.g., hermetically sealed,to prevent or limit exchange of air, water or other gases between thecontainer's contents and air. Extemporaneous injection solutions andsuspensions are prepared from sterile powders, granules and tablets asdescribed above. Unit dosage formulations are those containing a dailydose or unit daily sub-dose, as recited herein, or an appropriatefraction thereof, of the F1C(s).

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents or excipients conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents. Excipients include liquids,such as benzyl benzoate, cottonseed oil, N,N-dimethylacetamide, a C₂₋₁₂alcohol (e.g., ethanol), glycerol, peanut oil, vitamin E, poppyseed oil,safflower oil, sesame oil, soybean oil and vegetable oil. Excipients mayoptionally exclude one or more excipient, e.g., chloroform, dioxane,vegetable oil, DMSO, other excipients or any combination of these. Otherexcipients are components typically used in the pharmaceuticalformulation arts, e.g., one, two or more of fillers, binders,disintegrants, dispersants, preservatives, glidants and lubricants,e.g., povidone, crospovidone, corn starch, carboxymethyl cellulose,hydroxypropyl methylcellulose, microcrystalline cellulose, gum arabic,polysorbate 80, butylparaben, propylparaben, methylparaben, BHA, EDTA,sodium lauryl sulfate, sodium chloride, potassium chloride, titaniumdioxide, magnesium stearate, castor oil, olive oil, vegetable oil,buffering agents such as sodium hydroxide, monobasic sodium phosphate,dibasic sodium phosphate, potassium hydroxide, monobasic potassiumphosphate, dibasic potassium phosphate, tribasic potassium phosphate,potassium carbonate, potassium bicarbonate, ammonium hydroxide, ammoniumchloride, saccharides such as mannitol, glucose, fructose, sucrose orlactose any of which may be compressible or any of which may be spraydried, milled, micronized or otherwise treated to obtained desiredcharacteristics.

Formulations made from or comprising a F1C are optionally stored underconditions that limit the amount of light or water that reaches theformulation, e.g., in a sealed container that holds a formulation orunit dosage form and optionally contains silica gel or activated carbon.Water permeation characteristics of containers have been described,e.g., Containers—Permeation, Chapter, USP 23, 1995, U.S. PharmacopeialConvention, Inc., Rockville, Md., p. 1787. Storage of BrEA hemihydrateor formulations that contain it is typically at about 4-30° C.

The invention further provides veterinary compositions comprising atleast one F1C together with a veterinary excipient(s) therefor.Veterinary excipients are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials that are otherwise inert or acceptable in the veterinary artand are compatible with the F1C(s). These veterinary compositions may beadministered orally, parenterally or by any other desired route.

Invention formulations include controlled release or slow releaseformulations containing a F1C(s) in which the release of the F1C(s) iscontrolled or regulated to allow less frequency dosing or to improve thepharmacokinetic or toxicity profile of a given F1C(s). Polymers andother materials that are suitable to prepare controlled releaseformulations that comprise a F1C have been described, e.g., U.S. Pat.Nos. 4,652,443, 4,800,085, 4,808,416, 5,013,727, 5,188,840.

Formulations may thus contain microcapsules, granules or other shapedforms and may comprise a F1C and a slow release polymer or polymermatrix that comprises or consists of one or more of ethylenedimethacrylate, diethylene glycol dimethacrylate, diethylene glycoldiacrylate, triethylene glycol dimethacrylate, triethylene glycoldiacrylate, tetrathylene glycol dimethacrylate, tetraethylene glycoldiacrylate, polyethylene glycol dimethacrylate, polyethylene glycoldiacrylate, diethylaminoethyl dimethacrylate, glycidyl methacrylate,epoxy acrylate, glycidyl acrylate, hydroxyethyl methacrylate,hydroxyethyl acrylate, hydroxypropyl methacrylate, hydroxypropylacrylate, hydroxybutyl methacrylate, hydroxybutyl acrylate, hydroxyhexylmethacrylate, hydroxyhexyl acrylate, butanediol dimethacrylate,butanediol diacrylate, propanediol dimethacrylate, propanedioldiacrylate, pentanediol dimethacrylate, pentanediol diacrylate,hexanediol dimethacrylate, hexanediol diacrylate, neopentyl glycoldimethacrylate, neopentyl glycol diacrylate, trimethylopropanetriacrylate, trimethylolpropane trimethacrylate, trimethyloethanetriacrylate, trimethylolethane trimethacrylate, polypropyleneglycoldiacrylate, and polypropylene glycol dimethacrylate.

Formulations may comprise a liposome or lipid complex that comprises orcontains a F1C(s). Such formulations are prepared according to knownmethods, e.g., U.S. Pat. Nos. 4,427,649, 5,043,165, 5,714,163,5,744,158, 5,783,211, 5,795,589, 5,795,987, 5,798,348, 5,811,118,5,820,848, 5,834,016 and 5882678. The liposomes optionally contain anadditional therapeutic agent(s), e.g., amphotericin B, cis-platin,adriamycin, a protease inhibitor, a nucleoside or a nucleotide analog,such as one of those mentioned herein. Formulations that compriseliposomes can be delivered to a subject by any standard route, e.g.,oral, aerosol or parenteral (e.g., s.c., i.v. or i.m.).

Liposome formulations can be used to enhance delivery of the F1C(s) tocertain cell types such as tumor cells (see e.g., U.S. Pat. No.5,714,163) or to cells of the reticuloendothelial system (“RES”). TheRES includes macrophages, mononuclear phagocytic cells, Kupfer cells,cells lining the sinusoids of the spleen, lymph nodes, and bone marrow,and the fibroblastic reticular cells of hematopoietic tissues. Ingeneral, RES cells are phagocytic and they are targets for targeteddelivery of a F1C(s) in vitro or in vivo using liposomes, or othercompositions or formulations. Thus, one can deliver F1C to a neoplasmthat is derived from reticuloendothelial tissue (reticuloendothelioma).The liposomes may optionally comprise a peptide from an infectious agentsuch as a malaria parasite, a virus or a tumor associated antigen. Thepeptides may facilitate the generation of a MHC class II and B cellresponse. In other cases a liposomal F1C formulation is useful to obtainsuspension F1C formulations.

Invention embodiments include the product made by a process ofcombining, mixing or otherwise contacting a F1C and one, two or moreexcipients. Such products are produced by routine methods of contactingthe ingredients. Such products optionally contain a diluent, adisintegrant, a lubricant, a binder, or other excipients describedherein or in references cited herein.

Other embodiments include compositions that transiently occur when amethod step or operation is performed. For example, when a F1C,containing less than about 3% w/w water is contacted with an excipient,e.g., a PEG, an alcohol, propylene glycol benzyl alcohol or benzylbenzoate, the composition before addition of one ingredient with anotheris a non-homogenous mixture. As the ingredients are contacted, themixture's homogeneity increases and the proportion of ingredientsrelative to each other approaches a desired value. Thus, inventioncompositions, which contain less than about 3% w/w or less than about 2%w/w or less than about 1% w/w or less than about 0.5% w/w water cancomprise about 0.0001-99% w/w of a F1C and 1, 2, 3 or more excipients.These transient compositions are intermediates that necessarily arisewhen one makes an invention composition or formulation and they areincluded in invention embodiments.

When a F1C and an excipient(s) is contacted or mixed, the finalcomposition may comprise a homogenous mixture or it may comprise amixture that is not homogenous for one or more of the compounds that arepresent in the composition. Compositions and formulations that areeither homogenous or non-homogenous are included in the scope of theinvention. Non-homogenous compositions can be used, e.g., to makecontrolled release formulations.

Invention embodiments include compositions and formulations thatcomprise less than about 3% water, a F1C and a compound that is notgenerally considered suitable for human use but is useful to make aninvention formulation for veterinary use. Veterinary formulations arecompositions useful for the purpose of administering inventioncompositions to primates, cats, dogs, horses, cows, rabbits and othersubjects and may contain excipients acceptable in the veterinary art andare compatible with F1Cs. These veterinary compositions may not alwaysbe suitable for human use because they contain an excipient that is notsuitable for human use, e.g., an alcohol other than ethanol such asmethanol, propanol or butanol. Typically such excipients will be presentat relatively low levels, e.g., about 1-30%, usually about 1-5%.

Invention embodiments include non-aqueous compositions and formulations,e.g., unit dosage forms and sterile solutions or suspensions, thatcomprise about 1-25% w/w of a F1C, about 20-60% w/w propylene glycol,about 15-55% w/w of more or more PEGs, e.g., PEG100 or PEG200, about0-5% w/w benzyl benzoate, about 0-5% w/w benzyl alcohol and optionallyone or more additional excipients. These non-aqueous formulations willusually contain less than about 3%, 2%, 1%, 0.8%, 0.5%, 0.4%, 0.3%, 0.2%or 0.1% w/w of water. In formulations that contain non-aqueousexcipients, the F1C will usually be relatively hydrophobic and willusually not contain any easily charged or ionizable moieties such asfree carboxyl groups.

F1Cs may be administered to subjects by transmucosal dosing, e.g., bybuccal or sublingual administration. The buccal area generally refers tothe subject's mouth and pharynx, and the buccal mucosa includes themucosa of the mouth and pharynx. The sublingual area refers generally tothe mucosa below and adjacent to the tongue. Formulations suitable forbuccal or sublingual administration typically comprise about 1-100 mg ofF1C per unit dose, often about 2-60 mg. Transmucosal dosages maycomprise a slow release or a rapid release formulation or tablet thatcontains about 1, 5, 10, 15, 20, 25, 30, 35, 40, 50 or 60 mg of a F1C.Slow release formulations will generally degrade or release the F1C fromthe dosage over a period of about 2 minutes to about 60 minutes or more.Rapid release formulations will generally release the F1C over a periodof about 4 seconds to about 2 minutes, typically over about 0.1 to about1 minute. Solid and liquid buccal or sublingual formulations optionallyinclude one, two, three or more excipients such as fillers, binders,lubricants, antioxidants, preservatives, flavoring agents ordisintegrants, e.g., lactose, sucrose, mannitol, Tween-80, magnesiumstearate, butylated hydroxyanisole, butylated hydroxytoluene,cyclodextrins (e.g., α-cyclodextrins, β-cyclodextrins, γ-cyclodextrins,hydroxypropyl-β-cyclodextrin, β-cyclodextrin ether comprising one ormore hydroxybutyl sulfonate moieties, cyclodextrins as described in U.S.Pat. Nos. 6,610,671 or 6,566,347), carbomers, hydrolyzedpolyvinylalcohol, polyethylene oxide, polyacrylates,hydroxypropylmethylcellulose, hydroxypropylcellulose, and combinationsthereof. Such formulations may be a unit solid such as a tablet orpowder or a liquid. Buccal tablets may comprise a concave surface forcontacting the buccal mucosa and adhering to it. A buccal or sublingualdosage may comprise a compressed tablet of a substantially uniformmixture of a bioerodible polymeric carrier, which on sustained contactwith the oral mucosa, substantially or completely erodes within apredetermined period in the range of about 10 minutes to about 24 hours.In some embodiments, the F1C is administered by a method foradministering the compound to the subject, e.g., to a mammal or a human,comprising affixing a unit dosage or tablet to the subject's buccalmucosa in a region at or near the upper gum between the first bicuspidon the left and the first bicuspid on the right (or an alternativelocation for the dosage unit is the inner lip area opposing the thisupper gum area) and optionally allowing the tablet to remain in placeuntil erosion thereof is complete or nearly complete. Exemplaryexcipients may comprise a combination of polyethylene oxide and acarbomer, e.g., wherein the polyethylene oxide and the carbomer are inan approximately 1:5 to 5:1 ratio by weight.

Tablets or unit dosages for buccal or sublingual delivery may be about 5mm in diameter and 2 mm in height, so that the unit dosage occupiesabout 40 mm³. Such dosages will typically weigh less than about 100 mg(e.g., about 5 to 60 mg), with a contact surface area of about 10-30mm², e.g., about 15-20 mm². Such dosages will generally be about 4-10 mmin diameter and about 1-3 mm in height. When a polymer excipient isused, it optionally comprises a polymer having sufficient tack to ensurethat the dosage unit adheres to the buccal mucosa for a sufficient timeperiod, e.g., the time period during which drug is to be delivered tothe buccal mucosa. The polymeric excipient is gradually “bioerodible,”and it hydrolyzes, dissolves, erodes or disintegrates (collectively“erodes”) at a predetermined rate upon contact with water or saliva. Thepolymeric carrier is generally sticky when moist, but not when dry, forconvenience in handling. The average molecular weight of the polymer maybe about 400 to 1,000,000, or about 1,000 to 100,000. Higher themolecular weight polymers generally erode more slowly.

For these buccal and sublingual dosages, a pharmaceutically acceptablepolymer(s) can be used. Such polymers will provide a suitable degree ofadhesion and the desired drug release profile, and are generallycompatible with the drug to be administered and any other componentsthat may be present in the buccal dosage unit. The polymeric carriersoptionally comprise hydrophilic (water-soluble and water-swellable)polymers that adhere to the wet surface of the buccal mucosa. Examplesof polymeric carriers that are useful herein include acrylic acidpolymers, e.g., those known as “carbomers” (Carbopol™, which may beobtained from B.F. Goodrich, is one such polymer). Other suitablepolymers include hydrolyzed polyvinylalcohol; polyethylene oxides (e.g.,Sentry polyox™ water soluble resins, available from Union Carbide);polyacrylates (e.g., Gantrez™, which may be obtained from GAF); vinylpolymers and copolymers; polyvinylpyrrolidone; dextran; guar gum;pectins; starches; and cellulosic polymers such as hydroxypropylmethylcellulose, (e.g., Methocel™, which may be obtained from the DowChemical Company), hydroxypropyl cellulose (e.g., Klucel™, which may beobtained from Dow), hydroxypropyl cellulose ethers (see, e.g., U.S. Pat.No. 4,704,285 to Alderman), hydroxyethyl cellulose, carboxymethylcellulose, sodium carboxymethyl cellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate, cellulose acetate butyrate, andthe like. The carrier may also comprise two or more suitable polymers incombination, for example, a carbomer combined in an approximately 1:5 to5:1 ratio, by weight, with a polyethylene oxide.

Buccal dosages may contain only the F1C and the polymer(s). However, itmay be desirable in some cases to include one or more additionalexcipients. For example, a lubricant may be included to facilitate theprocess of manufacturing the dosage units; lubricants may also optimizeerosion rate and drug flux. If a lubricant is present, it may optionallyrepresent about 0.01 wt. % to about 2 wt. %, or about 0.01 wt. % to 0.5wt. %, of the dosage unit. Suitable lubricants include, but are notlimited to, magnesium stearate, calcium stearate, stearic acid, sodiumstearylfumarate, talc, hydrogenated vegetable oils and polyethyleneglycol. However, modulating the particle size of the components in thedosage unit and/or the density of the unit can provide a similar effect,e.g., improved manufacturability, and optimization of erosion rate anddrug flux without addition of a lubricant.

Other excipients are also optionally incorporated into buccal unitdosages. Such additional optional excipients include, one or moredisintegrants, diluents, binders, enhancers, or the like. Examples ofdisintegrants that may be used include, but are not limited to,cross-linked polyvinylpyrrolidones, such as crospovidone (e.g.,Polyplasdone™ XL, which may be obtained from GAF), cross-linkedcarboxylic methylcelluloses, such as croscarmelose (e.g., Ac-di-sol™,which may be obtained from FMC), alginic acid, and sodium carboxymethylstarches (e.g., Explotab™, which may be obtained from Edward Medell Co.,Inc.), methylcellulose, agar bentonite and alginic acid. Suitablediluents are those which are generally useful in pharmaceuticalformulations prepared using compression techniques, e.g., dicalciumphosphate dihydrate (e.g., Di-Tab™, which may be obtained fromStauffer), sugars that have been processed by cocrystallization withdextrin (e.g., co-crystallized sucrose and dextrin such as Di-Pak™,which may be obtained from Amstar), lactone, calcium phosphate,cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugarand the like. Binders, if used, are those that enhance adhesion.Examples of such binders include, but are not limited to, starch,gelatin and sugars such as sucrose, dextrose, molasses, and lactose.Permeation enhancers may also be present in the novel dosage units inorder to increase the rate at which the active agent passes through thebuccal mucosa. Examples of permeation enhancers include, but are notlimited to, polyethylene glycol monolaurate (“PEGML”), glycerolmonolaurate, lecithin, the 1-substituted azacycloheptan-2-ones,particularly 1-n-dodecylcyclaza-cycloheptan-2-one (available under thetrademark Azone™ from Nelson Research & Development Co., Irvine,Calif.), lower alkanols (e.g., ethanol), SEPA™ (available from MacrochemCo., Lexington, Mass.), cholic acid, taurocholic acid, bile salt typeenhancers, and surfactants such as Tergitol™, Nonoxynol-9™ andTWEEN-80™.

Flavorings are optionally included in buccal or sublingual formulations.Any suitable flavoring may be used, e.g., one or more of mannitol,sucrose, glucose, lactose, lemon, lemon lime, orange, menthol orartificial sweeteners such as aspartame, saccharin sodium, dipotassiumglycyrrhizinate, stevia and thaumatin. Some sweeteners such as sucrosemay also aid in dissolution or erosion of solid formulations. Coloringagents may also be added, e.g., any of the water soluble FD&C dyes ormixtures thereof, e.g., one or more of FD&C Yellow No. 5, FD&C RED No.2, FD&C Blue No. 2, etc., food lakes or red iron oxide. In addition suchformulations dosages may be formulated with one or more preservatives orbacteriostatic agents, e.g., methyl hydroxybenzoate, propylhydroxybenzoate, chlorocresol, benzalkonium chloride, or the like.

Other embodiments include solid buccal or sublingual formulationscomprising (i) a F1C and (ii) erythritol, (iii) crystalline celluloseand (iv) a disintegrant, e.g., crospovidone. These formulations arecapable of buccal disintegration or dissolution and may further comprisemannitol. These formulations may dissolve completely in solely salivawithin about 1-10 minutes of administration to a subject. The erythritolis optionally contained in a proportion of about 5-90 parts by weight,based on 100 parts by weight of the solid buccal formulation. Thecrystalline cellulose is optionally contained in a proportion of about3-50 parts by weight, based on 100 parts by weight of the formulation.The disintegrant is optionally contained in a proportion of 1-10 partsby weight. In any of the solid buccal or sublingual formulations theingredients are generally uniformly mixed, although non-uniform mixturesmay be used. An exemplary formulation comprises a solid capable ofbuccal disintegration or dissolution, which comprises (i) about 0.3-50parts by weight of a F1C, (ii) about 50-80 parts by weight oferythritol, (iii) about 5-20 parts by weight of crystalline celluloseand (iv) about 3-7 parts by weight of a disintegrant, which optionallyis one or more of crospovidone, croscarmellose, croscarmellose sodium,carmellose calcium, carboxymethylstarch sodium, low substitutedhydroxypropyl cellulose or corn starch. Examples of the crystallinecellulose include products of various grade such as CEOLUS KG801, avicelPH101, avicel PH102, avicel PH301, avicel PH302, avicel RC-591(crystalline cellulose carmellose sodium) and so on. One crystallinecellulose may be used or two or more species may be used in combination.The disintegrant, e.g., crospovidone, may be used singly or incombination with other disintegrants. Crospovidone includes anycross-linked 1-ethenyl-2-pyrrolidinone homopolymer, and may comprise apolymer of molecular weight of 1,000,000 or more. Examples ofcommercially available crospovidone include Cross-linked povidone,Kollidon CL, Polyplasdone XL, Polyplasdone XL-10, INF-10 (manufacturedby ISP, Inc.), polyvinylpolypyrrolidone, PVPP and1-vinyl-2-pyrrolidinone homopolymer. The disintegrants are optionallyincorporated in a proportion of about 1-15 parts by weight, or about1-10 parts by weight, or about 3-7 parts by weight, based on 100 partsby weight of the solid formulation.

Some embodiments include a solid buccal or sublingual formulationcontaining a F1C where unit doses of the formulation substantially orcompletely disintegrates or erodes within about 20-120 seconds in waterat 37° C. or on insertion of the unit dose into the buccal area or uponplacement under the tongue. Such formulations may comprise a swellablehydrophilic excipient, a water-soluble or a water-dispersible excipient,e.g., one or more of partially hydrolyzed gelatin, hydrolyzed dextran,dextrin, mannitol, alginates, polyvinyl alcohol, polyvinyl pyrrolidine,water soluble cellulose derivatives, methylcellulose, ethyl cellulose,carboxymethyl cellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, alginates, gelatin, guargum, gum tragacanth, gum acacia, polyacrylic acid, polymethacrylic acid,polysilicic acid, polylactic acid, polymaleic acid, polyvinyl alcohol,polyethylene glycol, polyvinyl pyrrolidone, nonionic blocked polymers,carbomers, polycarbophils, a water soluble starch, dicalcium phosphate,calcium carbonate, silica or polyethyleneglycol, e.g., PEG1000, PEG2000or a polyethylene oxide (“PEO”), PEO1000, PEO100000 or PEO5000000.

Other embodiments include the product obtained by storing inventioncompositions or formulations, e.g., unit dosage forms or compositionsused to make formulations, at about 4-40° C. for at least about 30 days,e.g., storage at ambient temperature for about 1-24 months. Inventionformulations will typically be stored in hermetically or inductionsealed containers for these time periods. Compositions and formulationsthat comprise a F1C will typically be held in closed or sealedcontainers, particularly when the composition is a formulation forpharmaceutical or veterinary use.

Typical containers for storage of compositions and formulations thatcomprise a F1C will limit the amount of water that reaches the materialscontained therein. Typically, formulations are packaged in hermeticallyor induction sealed containers. The containers are usually inductionsealed. Water permeation characteristics of containers have beendescribed, e.g., Containers—Permeation, chapter, USP 23 <671>, UnitedStates Pharmacopeial Convention, Inc., 12601 Twinbrook Parkway,Rockville, Md. 20852, pp.: 1787 et seq. (1995).

Immune modulation. The F1Cs, or the biologically active substancesproduced from these compounds by hydrolysis or metabolism in vivo, havea number of clinical and non-clinical applications. The compounds aregenerally useful to correct immune dysregulation, e.g., imbalancedimmune responses to disease conditions, pathogens or the like,suppression of an innate or acquired immune response(s) and inflammationconditions in vertebrate or mammalian subjects, e.g., as disclosedherein. Thus, while the compounds will generally enhance a deficientimmune response in a given clinical condition, they will generallyreduce the same immune response when it is too active in a differentclinical condition. For example, they can enhance insufficient orsuboptimal Th1 immune responses, reduce excess or undesirable Th2 immuneresponses, reduce excess or undesirable Th1 immune responses or enhanceinsufficient or suboptimal Th2 immune responses or they can reduceexcess or undesirable inflammation or one or more of its symptoms. Thecompounds will generally also modulate dysregulated Tc1 and Tc2 immuneresponses (associated with CD8⁺ T cells) in a similar manner, e.g.,excessive Tc1 or Tc2 responses will be detectably decreased anddeficient or suboptimal Tc1 or Tc2 responses will generally bedetectably enhanced.

Invention embodiments include a method to modulate a subject's innateimmunity, Th1 immune responses, Tc1 immune responses, Th2 immuneresponses or Tc2 immune responses comprising administering an effectiveamount of a F1C to a subject or delivering the F1C to the subject'stissues. Other methods include modulating an immune or cellular responsein a subject in need thereof comprising administering to the subject, ordelivering to the subject's tissues, an effective amount of a compoundof formula 1. Immune and cellular response modulation includes enhancingTh1 immune responses, reducing Th2 immune responses, reducing Th1 immuneresponses, enhancing Th2 immune responses, reducing unwanted orpathological inflammation, enhancing hematopoiesis or modulating thesynthesis, level or a biological activity of a biomolecule such as (1) atranscription factor such as a nuclear hormone receptor or an associatedreceptor factor, (2) a purine such as adenosine, (3) a nucleotidecofactor such as NADPH, (4) a cytokine or interleukin or a receptor fora cytokine or interleukin, or (5) another biomolecule as disclosedherein. Such enhancements, reductions, levels or activities are usuallyin an easily detectable range, e.g., a change compared to a suitablecontrol of at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,90%, 95% or a range that is between about any two of these values.Typically the subject is in need of such treatment, e.g., by having aclinical condition disclosed herein or being subject to developing sucha condition, e.g., having been exposed or potentially exposed to apathogen or having a predisposing condition such as precancer.

In modulating one or more activities of Th1, Th2, Tc1 or Tc2 cells ortheir function(s), the F1Cs will typically detectably modulate one, two,three or more factors, e.g., immune cell subsets or populations,cytokines, interleukins, surface antigens such as a CD molecule(s)and/or their receptors that affect the development, migration, numbersor biological function(s) of such cells. When a Th1 or Tc1 cell orpopulation is affected, the F1Cs will typically increase or decrease thesynthesis or level of one, two or more of an associated effector factor,e.g., IFNγ, IL-2, IL-12, IL-18, T-bet, PPARα and PPARγ or a cell surfacemolecule, e.g., as disclosed herein or in the cited references, that isassociated with or needed for normal, optimal or enhanced Th1 or Tc1cells or cell function. Such molecules are generally associated withdevelopment or enhancement of Th1 or Tc1 cells or their biologicalfunction(s). When a Th2 or Tc2 cell or population is affected, the F1Cswill typically increase or decrease the synthesis or level of one, twoor more of an associated effector factor, e.g., IL-4, IL-5, IL-6, IL-8,IL-10, IL-13, GATA-3, COX-2 or a cell surface molecule, e.g., asdisclosed herein or in the cited references, that is associated with orneeded for normal, optimal or enhanced Th2 or Tc2 cells or cellfunction(s). Such molecules are generally associated with development orenhancement of Th2 or Tc2 cells or their biological function(s).

Similarly, when a subject has or is subject to developing an unwanted orexcessive inflammation, the F1Cs will generally detectably modulate oneor more relevant effector factors for inflammation, e.g., a detectabledecrease of one, two, three or more of IL-1α, IL-1β, TNFα, TNF-β,MIP-1α, MIP-2, TGF-β1, IP-10, LT-β, γIFN, IL-6, IL-8, IL-10 and COX-2,lipoxygenase, or an increase of one or more suppressor factors orantagonists of inflammation. Such modulation can comprise increases ordecreases of at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%,60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100%, 200%, 300%, 500%, 1000%,5000% or within a range between any two of these values, e.g., betweenabout 5-95%, about 10-90%, about 5-60% or about 40-95%. In general, suchchanges leads to a detectable amelioration of an inflammation-associateddisease, condition, symptom or to the detectable slowing of theprogression thereof or to a detectably reduced incidence or severity ofor susceptibility to developing an unwanted inflammatory response.

In conditions where an unwanted or excessive Th1, Tc1, Th2 or Tc2response is associated with or causes a disease(s), disease(s)progression, disease(s) state maintenance, condition(s) or symptom(s),the F1Cs will generally decrease the level or one or more biologicalactivity of one, two or more of their respective associated effectormolecules. In conditions where a deficient or suboptimal Th1, Tc1, Th2or Tc2 response is associated with or causes a disease(s), disease(s)progression, disease(s) state maintenance, condition(s) or symptom(s),the F1Cs will generally increase the level or one or more biologicalactivity of one, two, three or more of their respective associatedeffector molecules. Such changes in the level or biologicalactivity(ies) the associated effector molecules is generally detectableusing standard methods and is typically an increase (when a response isinsufficient) or a decrease (when a response is in excess) of at leastabout 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%,85%, 90%, 95%, 98% or within a range between any two of these values,e.g., between about 5-95%, about 10-90%, about 5-60% or about 40-95%. Ingeneral, such changes leads to a detectable amelioration of a disease,condition, symptom or to the detectable slowing of the progressionthereof or to a detectably reduced incidence or severity of orsusceptibility to developing a disease(s) or the occurrence of asymptom(s) for a at least a portion of subjects that are treated with aF1C, e.g., at least about 5%, 10%, 20%, 40%, 60% or 80% of treatedsubjects. The F1Cs may facilitate the clinical cure of a disease(s),prolong remission of a disease(s) or eliminate or ameliorate aclinically detectable symptom(s).

The F1C will generally also affect the function of other immune cellsubsets in a similar manner. Thus, when an insufficient macrophage,dendritic cell or neutrophil response is associated with theestablishment, maintenance or progression of a disease, symptom or acondition, the F1Cs will generally enhance of the level or a biologicalactivity(ies) of one or more effector molecule associated with or neededfor an optimal or more normal response or immune function that ismediated by the macrophages, dendritic cells or neutrophils. Similarly,when the subject suffers from a excessive or pathological activityassociated with macrophages, dendritic cells or neutrophils, which isassociated with the establishment, maintenance or progression of adisease, symptom or a condition, the F1Cs will generally detectablyreduce the level or a biological activity(ies) of one or more effectormolecule associated with or needed for an optimal or more normalresponse or immune function that is mediated by the macrophages,dendritic cells or neutrophils. Such effector molecules are as describedherein or in the cited references.

As used herein, reference to Th1 or Th2 immune responses means suchresponses as observed in mammals generally and not as observed in themurine system, from which the Th1 and Th2 terminology originated. Thus,in humans, Th1 cells are CD4⁺ T lymphocytes and they usuallypreferentially display chemokine receptors CXCR3 and CCR5, while Th2cells are CD4⁺ T lymphocytes and usually preferentially express theCCR4, CCR8 and/or CXCR4 chemokine receptor molecule(s) and generally asmaller amount of CCR3, see, e.g., U. Syrbe et al., Springer Semin.Immunopathol. 1999 21:263-285, S. Sebastiani et al., J. Immunol. 2001166:996-1002. Tc1 and Tc2 immune responses are mediated by CD8⁺lymphocytes and means to identify these cells and their associatedlymphokines, cell specific antigens and biological activities have beendescribed, see, e.g., M. B. Faries et al., Blood 2001 98:2489-2497, W.L. Chan et al., J. Immunol. 2001 167:1238-1244, C. Prezzi et al., Eur.J. Immunol. 2001 31:894-906, H. Ochi et al., J. Neuroimmunol. 2001119:297-305, D. H. Fowler and R. E. Gress, Leukemia and Lymphoma 200038:221-234.

The F1Cs are useful in reestablishing normal immune function in variousimmune dysregulation or immune suppression conditions. For example, theyare useful to treat, slow progression of or to ameliorate one or moresymptoms associated with one or more of an autoimmune condition(s), ainflammation condition(s), an infection(s), a cancer(s), a precancer(s),a chemotherapy(ies), radiation therapy, a burn(s), a trauma(s), asurgery(ies), a pulmonary condition, a cardiovascular disease(s) and aneurological or neurodegenerative disease(s). Without being limited toany theory, the F1Cs are believed to act through several mechanisms,including by directly or indirectly modulating nuclear hormone receptoractivity or by affecting or modulating other biological targets such astranscription factors, steroid binding proteins or enzymes in at leastsome of the diseases, conditions or symptoms disclosed herein.

The F1Cs are useful to modulate delayed-type hypersensitivity (“DTH”)responses and anergic conditions in subjects having to subject todeveloping abnormal DHT responses or anergy. Means to measure suchresponses and conditions are known and can be used to characterize theeffects of the F1Cs on these responses and conditions. See, e.g., A. E.Brown, et al., J. Med. Assoc. Thailand 83:633-639 2000, R. A. Smith etal., J. Adolesc. Health 27:384-390 2000, N. M. Ampel, Med. Mycology37:245-250 1999. The compounds will generally detectably enhance orrestore DTH in immune suppression conditions. They will also generallydetectably reduce or eliminate anergy in subjects having significantlyreduced or no immune response to, e.g., specific antigens or pathogens.

The invention provides a method to detectably enhance an antigenspecific immune response, cell mediated immune response or adelayed-type hypersensitivity immune response in a subject havingimpaired or negligible antigen specific immune response, cell mediatedimmune response or delayed-type hypersensitivity immune response,comprising administering to the subject, or delivering to the subject'stissues, an effective amount of a F1C. The antigen specific immuneresponse, cell-mediated immune response or delayed-type hypersensitivityimmune response can be enhanced at least about 25%, at least about 40%,at least about 50%, at least about 60%, at least about 75% or at leastabout 90%. Some of the subjects may have an antigen specific immuneresponse, cell mediated immune response or a delayed-typehypersensitivity immune response that is impaired or negligible, e.g.,about 50% or less or about 30% or less or about 10% or less of theresponse that an otherwise normal subject would be expected to have.Such subjects may not detectably respond to at least 1 antigen out of 2,3, 4 or 5 antigens that a normal subject would respond to. In someembodiments, the subject is an HIV-infected human having a CD4⁺ T cellcount of about 0-150 cells/mm³ or about 2-100 cells/mm³ and/or whereinthe antigen specific immune response, cell mediated immune response ordelayed-type hypersensitivity immune response is an enhanced response toa viral, bacterial, parasite or fungal antigen such as an HIV, HCV, HBVor CMV antigen such as a viral or HIV core antigen or HIV p24 antigen ora viral or HIV envelope antigen, a Candida antigen, a viral, bacterial,parasite or fungal antigen essentially as described herein or tophytohemagglutinin. The responses to treatment with a F1C may bequantitated by, e.g., mixed lymphocyte reaction, ELIspot analysis orflow cytometric analysis of, e.g., circulating blood cells such as CD4⁺or CD8⁺ T cells or for levels of cytokines (e.g., IL-2, TNFα or IFNγ) insuch cells. Such analyses have been described, e.g., V. P. Badovinac andJ. T. Hardy, J. Immunol. Methods 2000, 238:107-117, N. Favre et al., J.Immunol. Methods 1997, 204:57-66, E. Hagiwara et al., Cytokine 1995,7:815-822, N. W. Lukacs et al., Blood 1993, 82:3668-3674, M. Umemoto etal., Clin. Exp. Immunol. 1998, 112:459-463, A. Fietta et al.,Gerontology 1994, 40:237-245, C. H. Orteu et al., J. Immunol. 1998,161:1619-1629.

Clinical indications that have an association with or have a symptom(s)that is consistent or associated with an excessive or unwanted Th2immune response include, e.g., fatigue, pain, fever or an increasedincidence of infection, schizophrenia, acute myelitis, tumorprogression, progressive systemic sclerosis, Omenn's syndrome, atopicdisease, atopy, allergen hypersensitivity, atopic asthma, atopicdermatitis, burns, trauma (e.g., bone fracture, hemorrhage, surgery),immune responses to xenotransplantation, chronic periodontitis, SLE(systemic lupus erythematosus), discoid lupus erythematosus,osteoporosis, myasthenia gravis, Graves disease, mite-associatedulcerative dermatitis, rheumatoid arthritis and osteoarthritis.Excessive Th2 immune responses are also associated with an unwantedsymptom or pathology, e.g., fatigue, pain, fever or an increasedincidence of infection, that is associated with aging, allergy andinflammation conditions such as allergic bronchopulmonary aspergillosisin cystic fibrosis patients, allergic respiratory disease, allergicrhinitis, atopic dermatitis, subepithelial fibrosis in airwayhyperresponsiveness, chronic sinusitis, perennial allergic rhinitis,fibrosing alveolitis (lung fibrosis). This common underlying immunecomponent is at least part of the pathology or symptoms of all of theseconditions. This allows a F1C to be effectively used to prevent or treatthe condition or to treat or ameliorate one or more symptoms that areassociated with these conditions. Thus, in some embodiments, an unwantedor excessive Th2 response is present and amelioration of one or moresymptoms associated with this condition is accomplished by administeringan effective amount of a F1C according to the methods described herein,e.g., F1C is administered using a formulation and a route ofadministration essentially as described herein on an intermittent or adaily basis.

Typically, unwanted Th2 immune responses are associated with, or causedby, increased expression of one or more cytokines or interleukins suchas one, two, three or more of cortisol, IL-4, IL-5, IL-6, IL-10 andIL-13. Administration of a F1C will generally reduce the expression ofone or more of the Th2-associated cytokines or interleukins. At the sametime, the compounds generally enhance the expression of one or morecytokines or interleukins associated with Th1 immune responses. Becauseof their capacity to modulate or to balance Th1 and Th2 immuneresponses, the compounds are useful for a variety of clinicalconditions, e.g., infection, immunosuppression or cancer, where anenhanced Th1 immune response is desired. Effects of the F1Cs intreating, preventing or slowing the progression of the clinicalconditions described herein can include one or more of (1) enhancing theTh1 character of a subject's immune response or immune status, (2)increasing the intensity of a Th1 or a Th2 immune response or both and(3) decreasing inflammation or a symptom thereof.

Exemplary conditions where an immune imbalance or an excessive Th1immune response is involved include autoimmune diseases such as multiplesclerosis, Crohn's disease (regional enteritis), ulcerative colitis,inflammatory bowel disease, rheumatoid arthritis, reactive arthritis,acute allograft rejection, sarcoidosis, type 1 diabetes mellitus,Helicobacter pylori associated peptic ulcer, graft versus host diseaseand Hashimotos' thyroiditis. Because these conditions are associatedwith a similar type immune dysfunction, a F1C can be effectively used toprevent or treat these conditions or to treat or ameliorate one or moresymptoms associated therewith. Thus, in some embodiments, an unwanted orexcessive Th1 response is present and amelioration of one or moresymptoms associated with this condition is accomplished by administeringan effective amount of a F1C according to the methods described herein,e.g., F1C is administered using a formulation and a route ofadministration essentially as described herein on an intermittent or adaily basis. In other embodiments, an deficient Th1 response isenhanced, which is optionally observed as a detectable increase in oneor more of IFNγ, IL-2, IL-12 or IL-18 in Th1 cells or in accessory cellssuch as a dendritic cell or macrophage. In all of the conditions wherean insufficient or excess Th1, Th2, Tc1 or Tc2 response is present,amelioration of one or more symptoms associated with the condition isaccomplished by administering an effective amount of a F1C according tothe methods described herein.

Aspects of the invention include the use or administration ofcompositions or formulations that comprise a carrier and an amount of atleast one F1C effective to detectably modulate an immune parameter. Forexample, to enhance the relative proportion of a desired immune cellsubset, e.g., CD4⁺ T cells, CD8⁺ T cells, NK cells, LAK cells,neutrophils, granulocytes, basophils, eosinophils or dendritic cells, orto modulate (detectably increase or decrease) one or more functions ofimmune cell subsets. The F1Cs can modulate the expression of CDmolecules or alter the proportion of cell subsets, e.g., CD4⁺ or CD8⁺ Tcells, or their relative numbers in a subject's blood or tissues. CD andrelated molecules participate in the function of various immune cellsubsets and can be useful as markers for immune function in vivo. Insome aspects, the F1Cs activate immune cells which generally alters(increases or decreases) expression of, or changes the numbers of cellsthat express one or more of, CD4, CD6, CD8, CD25, CD27, CD28, CD30,CD36, CD38, CD39, CD43, CD45RA, CD45RO, CD62L, CD69, CD71, CD90 orHLA-DR molecules. Often, the numbers of cells that express thesemolecules are increased, e.g., CD25, CD36, CD16 or CD69. Typically, suchincreases are observed as an increased proportion of circulating whiteblood cells that express one or more of these molecules or white bloodcells, e.g., T cells or dendritic cells, that express CXCR3, CCR5, CCR4,CCR8 and/or CXCR4. In some cases the number of such molecules per cellis detectably altered.

Expression of one or more adhesion molecules CD2, CD5, CD8, CD11a,CD11b, CD11c, CD18, CD29, CD31, CD36, CD44, CD49a, CD49b, CD49c, CD49d,CD49e, CD49f, CD50, CD54, CD58, CD103 or CD104 are also detectablymodulated after administration of the F1Cs to a subject. Often, thenumbers of cells that express these molecules are increased, e.g., CD5or CD56. The adhesion molecules function in various aspects of immuneresponses, such as binding to class I MHC molecules, transducing signalsbetween cells or binding to molecules in the extracellular matrixassociated with endothelial or other cell types. Administration of theF1Cs to a subject also affects the numbers of certain immune cellsubsets, e.g., NK cells (e.g., CD8⁻, CD56⁺ or CD8⁺, CD56⁺) or lymphokineactivated killer cells (LAK). Increased circulating NK or LAK cells aretypically observed, which is reflected in increased numbers of cellsthat express one or more of CD16, CD38, CD56, CD57 or CD94. Also,increased numbers of circulating dendritic cell precursors are observed,as shown by increases in cells that express one or more of CD11c, CD80,CD83, CD106 or CD123. Although one can observe an increased proportionof circulating white blood cells that express one or more of thesemolecules, in some instances the number of such molecules per cell isdetectably altered. Both the cell numbers and the density of CD moleculeper cell can also be detectably modulated. Modulation of immune cellsubsets typically occurs on intermittent dosing of a F1C, but will arisefrom any suitable dosing regimen, e.g., as described herein.

Expression of one or more homing or other receptors or receptor subunitssuch as CD62L, CLA-1, LFA1, CD44, ICAM, VCAM or ECAM may also bedetectably affected after administration of the F1Cs to a subject. Thenumbers of cells that express these molecules, or the relative amountsper cell of, e.g., CD44 or CD62L, may be increased where a desiredimmune response is desired, e.g., migration of T cells to mucosaltissues or exposure of naïve T cells to antigen in lymph nodes.Alternatively, numbers of cells that express these molecules, or therelative amounts per cell of, e.g., CLA-1, may be decreased whereinhibition of an undesired immune response, such as an inflammatoryresponse is desired. The subject's response to such enhanced expressionincludes migration of cells such as movement of naïve T cells toperipheral lymph nodes in response to modulation of CD62L or otherhoming receptor expression. Thus, the F1Cs can also facilitate migrationof various immune cell types, e.g., dendritic cells, NK cells, LAKcells, macrophages or lymphocytes, from one location to another within asubject. For example, the compounds can enhance dendritic cell orlymphocyte migration from areas such as the skin tissues to the gutassociated lymphoid tissue (“GALT”), lymph nodes or spleen. Suchmigration may facilitate the function of those cell types by increasingtheir transit to tissues where their effector functions, e.g., antigenpresentation by dendritic cells, normally occur. The migration period isoften relatively transient (e.g., observable over about 1-7 days) oroccasionally longer (e.g., occurring for about 8-40 days), depending onthe dosing regimen and other factors. This migration can be observed bystandard methods, e.g., by cell staining, by PCR analyses or bydetermining the presence of a given cell type in circulation ordetermining a decrease in the number circulating cells. A decrease wouldgenerally reflect sequestration of an immune cell population(s) in atissue(s) where the immune cell normally exercises its effectorfunctions.

Thus, in some embodiments, the migration of one or more immune cellsubsets such as CD11C⁺ cells from tissue such as skin or lung throughthe blood to immune tissue such as lymph nodes or GALT is seen as atransient increase in the level of circulating CD11C⁺ cells in responseto exposure of the subject's tissues to a suitable amount of a F1C.Thus, the level of CD11C⁺ cells in the blood will generally detectablyincrease, e.g., a statistically significant increase, plateau and thendecrease as migration of the cells to immune tissue subsides. In theseembodiments, the proportion of the cells of the affected immune cellsubset is typically relatively low in most physiological immune states,e.g., normal or abnormal immune conditions, compared to the total whiteblood cell population in circulation. In other embodiments, themigration of one or more immune cell subsets such as CD123⁺ cells fromthe circulation to immune tissue such as lymph nodes or GALT results ina decrease. In these embodiments, the decrease in the numbers ofcirculating immune cells reflects the migration of the immune cells fromthe blood to immune tissue such as lymph nodes or GALT. Such a decreasemay be transient and followed by recovery of the affected immune cellsubset(s) over about 2 to 24 weeks. In conducting these embodiments,administration of the F1C to the subject is accomplished using theformulations or the methods as described herein.

Thus, an aspect of the invention is a method to enhance the migration ofone or more immune cell types in a subject from one location (e.g., bonemarrow, circulating blood or a tissue such as the skin, liver, centralnervous system or lung) to another (e.g., to the blood or to a lymphoidtissue such as a lymph node, spleen or a mucosal tissue such as GALT) byadministration to a subject as described herein of an effective amountof a F1C essentially as described by any of the methods disclosedherein. A related aspect is the monitoring, e.g., by suitable bloodcounts or tissue biopsy, of the subject's response to determine thetiming and extent of such immune cell migration.

Other CD molecules that are modulated by the presence of the F1Cs in asubject include cytokine receptor molecules such as one or more ofCD115, CDW116, CD117, CD118, CDW119, CD120a, CD120b, CD121a, CD121b,CD122, CD123, CD124, CD125 CD126, CDW127, CDW128 or CDW130. Often, thenumbers of receptor molecules per cell will be modulated. For example,receptors for cytokines that mediate or facilitate Th1 immune responsesor innate immune responses (e.g., one or more of IL-1α, IL-1β, IL-2,IL-4, IL-12, γIFN or α-interferon) will typically increase in or oncells that mediate Th1 or innate immune responses. Modulation of thesemolecules may be by direct interactions with a receptor(s) in the cellthat expresses the cytokine receptor or indirectly by modulation ofcytokine synthesis in the affected cells or in other cells, typicallyimmune cells that may interact with the cells whose receptor synthesisis being modulated. Thus, autocrine or paracrine mechanisms may underliesome of the effects associated with administration of a F1C(s) such asaltered cytokine profiles in immune cells or altered immune cellpopulations. Endocrine cytokine mechanisms may also contribute todesired immune responses.

Treatment of a subject with a F1C can result in a change of at leastabout 20-80% or about 25-50% above or below (e.g., at least 30% or atleast 40% above or below) the control or basal level of affected immunecell subsets. For example, increases of more than about 30% in the totalnumbers of activated CD8⁺ T cells, e.g., CD8⁺, CD69⁺, CD25⁺ T cells,CD8⁺, CD69⁺, CD25⁻ T cells or CD8⁺, CD69⁻, CD25⁺ T cells, can occur by 7days after a single dose of a F1C to a subject. Such increases may begreater than 50%, 60% or 100% in the total numbers of activated CD8⁺ Tcells or subsets of activated CD8⁺ T cells in individual subjects.Typically such increases are about in the total numbers of activatedCD8⁺ T cells or subsets of activated CD8⁺ T cells averages about 30-40%,with individual subjects experiencing increases over 100% in the numbersof activated CD8⁺ T cells per unit blood volume compared to the basallevel.

Administration of the F1Cs can affect other immune cell subsets. Forexample, the concentration of circulating CD4⁺, CD69⁺, CD25⁻ (Th1 helpercells) and CD8⁺, CD16⁺, CD38⁺ LAK cells or CD8⁻, CD16⁺, CD38⁺ LAK cellstypically increases during or after the course of dosing a subject witha F1C. Also, CD8⁻, CD16⁺, CD38⁺ and CD8⁺, CD16⁺, CD38⁺ (ADCC effectorcells) and low side scatter Lin⁻, DR⁺, CD123⁺ (dendritic precursors) orlow side scatter Lin⁻, DR⁺, CD11c⁺ (dendritic cells or precursors) mayshow modest to significant increases.

In subjects that are immunosuppressed, e.g., from certain infections(e.g., viral (HIV, HCV), bacterial infection or parasite infection) orfrom chemotherapy (e.g., an antiviral therapy, a cancer chemotherapy ora radiation therapy), administration of the F1Cs to the subject resultsin a favorable shift in the balance of Th1 or Th2 responses the subjectcan mount in the face of immunosuppression. When Th1 responses aresuboptimal or insufficient, treatment with a F1C results in enhancementof Th1 responses or a reduction in Th2 responses. Conversely, when Th2responses are suboptimal or insufficient, treatment with a F1C resultsin enhancement of Th2 responses, which may occur with a concomitantmodulation (increase or decrease) in Th1 responses. The F1Cs can thus beused to shift the nature of a subject's immune response to result in amore balanced immune response from immunosuppression. Alternatively, thecompounds can selectively suppress inappropriate or unwanted immuneresponses. Enhanced Th1 responses appears to be at least partly due toone or more of (i) a reduction in biological restraints, e.g., highlevels of IL-4 or IL-10, on Th1 functions by preexisting primed Th1effector cells, (ii) enhanced differentiation of Th0 cells to Th1 cellsor enhanced responses mediated by Th1 cells, (iii) enhanced function ofaccessory cell function, e.g., antigen presentation by dendritic cells,dendritic precursor or progenitor cells or by macrophages or theirprecursors or progenitors, (iv) enhanced proliferation anddifferentiation of Th1 precursor or progenitor cells, (v) enhanced IL-12expression in dendritic cells or their precursors, which results inenhanced differentiation of Th1 cells from Th0 precursors, (vi) enhancedexpression or activity of factors associated with Th1 functions, e.g.,IL-2, gamma interferon (γIFN or IFNγ), IL-18 or lymphotoxin.

An aspect of the invention methods is an alteration in the expression ofIL-4 or IL-10 that occurs after administration of a F1C to a subject. Aconsistent observation is that extracellular IL-4 or IL-10 levelsrapidly decrease to levels that are undetectable by ELISA. IntracellularIL-10 levels are reduced to levels that are near or below the limits ofdetection by flow cytometry. The administration of a F1C to a subjectthus provides a means to inhibit either or both of these interleukins.Such inhibition may be associated with enhancement of Th1 immuneresponses relative to Th2 or Th0 responses, e.g., in subjects where Th1responses are suppressed (e.g., from viral, bacterial or parasiteinfection (HIV, HCV, etc) or chemotherapy) or are otherwise suboptimal.In many subjects, levels of either IL-4 or IL-10, usually IL-10, beforedosing with a F1C is low or undetectable. In these subjects, dosing withthe F1C results in a rapid drop in the interleukin that is detectable,usually IL-4.

Clinical conditions are described in more detail below where the F1Csare useful for treating, preventing, slowing the progression of, orameliorating one or more symptoms associated with the describedconditions. In any these conditions, any F1C disclosed herein can beused according to one or more of the dosing methods that are disclosedherein. For these conditions, dosages for the F1Cs, formulations androutes of administration are as described herein. Additional informationregarding these and other clinical conditions or symptoms that can betreated, prevented or ameliorated with the F1Cs are found at e.g., TheMerck Manual, 17^(th) edition, M. H. Beers and R. Berkow editors, 1999,Merck Research Laboratories, Whitehouse Station, N.J., ISBN0911910-10-7, or in other references cited herein.

Responses to treatment of a subject having a condition disclosed hereinwith a F1C is optionally monitored by observing changes in one or moreimmune or other appropriate clinical parameters, e.g., as describedherein or in D. S. Jacobs et al., editors, Laboratory Test Handbook,4^(th) edition, pages 11-686, Lexi-Comp Inc., Hudson, Ohio, ISBN0-916589-36-6, or in any of the references cited herein, or bymonitoring the progression or severity of the underlying conditionaccording to known methods, e.g., J. B. Peter, editor, Use andInterpretation of Laboratory Tests in Infectious Disease, 5^(th)Edition, pages 1-309, 1998, Specialty Laboratories, Santa Monica,Calif., ISBN 1-889342-13-0.

Infection treatments. In some embodiments, the F1C(s) is administered toa subject who has a pathogen infection, such as a viral, bacterial,fungal, yeast, intracellular parasite or extracellular parasiteinfection. The F1Cs can be considered for use in a broad scope ofinfections (see, e.g., J. B. Peter, editor, Use and Interpretation ofLaboratory Tests in Infectious Disease, 5^(th) edition, SpecialtyLaboratories, Santa Monica, Calif. 90404, 1998, pages 1-271), since thecompounds generally enhance Th1 immune responses and/or reduce Th2immune responses and/or reduce inflammation or its symptoms. Difficultyin treating many infections, e.g., progressive toxoplasmic encephalitis,malaria, tuberculosis, Leishmaniasis and schistosomiasis, often appearto be associated with one or more of an unwanted Th2 immune responses, asuboptimal Th1 response or the development of resistance of theinfectious agent to antimicrobial agents. For example, in disseminatedor diffuse tuberculosis, a reduced Th2 response would be desirable toallow a patient to slow progression of the disease or to clear infectedcells more efficiently. In treating chloroquine resistant or sensitivemalaria, the F1Cs have essentially the same activity.

Exemplary viral infections that the F1Cs can be used to treat, preventor ameliorate include infections by one or more DNA or RNA viruses, or asymptom(s) associated with such infection(s), such as a genogroup,clade, serotype, serotype subtypes, isolate, strain, subtype or so forthof influenza viruses (e.g., a human influenza A virus, a human influenzaB virus, an avian (e.g., chicken, duck, goose) influenza virus, a swineinfluenza virus or a recombinant avian-swine influenza virus),respiratory syncytial viruses, Rotaviruses, Hantaviruses, animal orhuman Papillomaviruses (e.g., HPV-1, HPV-2, HPV-6, HPV-7, HPV-10,HPV-11, HPV-13, HPV-16, HPV-18, HPV-32, HPV-33, HPV-35, HPV-39, HPV-42,HPV-43, HPV-44, HPV-45, HPV-61, HPV-72 or HPV-83), Poxviruses,Poliovirus, rabies viruses, human and animal Retroviruses (e.g., HIV-1,HIV-2, LAV, human T-cell leukemia virus I (“HTLV I”), HTLV II, HTLV II,SIV, SHIV, FIV or FeLV), Togaviruses and Flaviviruses (e.g., West NileVirus, Yellow Fever Virus, Dengue viruses), Herpesviruses (e.g., CMV,EBV, Varicella Zoster Virus (human Herpesvirus 3), Herpes simplex virus1 (“HSV-1”), Herpes simplex virus 2 (“HSV-2”), human Herpesvirus 6(“HHV-6”), human Herpesvirus 7, human Herpesvirus 8 (“HHV-8”)), measlesviruses, mumps viruses, rubella virus, Hepadnaviruses or hepatitisviruses, Adenoviruses, Retroviruses, Togaviruses, Alphaviruses,Arboviruses, Coronaviruses (e.g., human severe acute respiratorysyndrome virus, Urbani SARS-associated coronavirus, human respiratorycoronaviruses such as HCV-229E or HCV-OC43, including serogroups,genotypes, strains or variants of any of these viruses), Flaviviruses,Filoviruses, Rhinoviruses, Picornavi ruses, Papovavi ruses,Bunyaviruses, Picornaviruses, Poxviruses, Parvoviruses (e.g., human B19parvovirus) and/or Pestiviruses.

Specific viruses, including their genogroups, clades, isolates,serotypes, serotype subtypes, strains and so forth, that may establish avirus infection susceptible to the treatment methods disclosed hereininclude one or more of human hepatitis C virus (“HCV”), human hepatitisB virus (“HBV”), human hepatitis A virus (“HAV”), human hepatitis deltavirus, human hepatitis E virus, duck hepatitis virus, woodchuckhepatitis virus, one or more of human herpesviruses 1, 2, 3, 4, 5, 6A,6B, 7 or 8, human SARS virus, one or more of human papilloma viruses1-60, e.g., HPV 6, HPV 11, HPV 16, HPV 18, HPV 31, HPV 45, animalpapilloma viruses, poliovirus 1, poliovirus 2, poliovirus 3, one or moreof Dengue virus types 1, 2, 3 or 4, one or more of foot-and-mouthdisease virus 1-7, including serotypes O, A, C, SAT 1, SAT 2, SAT 3 andASIA 1, one or more of coxsackievirus A1-A22, A24, and B1-B6, one ormore of human echovirus 1-9, 11-27 and 29-34, one or more of humanenterovirus 68-71, one or more of adenovirus 1-49, one or more ofParainfluenza viruses 1, 2, 3 or 4, Human respiratory coronaviruses 229Eand OC43, one or more of Human rotaviruses, BK virus, Bunyamwera virus,California Encephalitis Virus, Central European Encephalitis Virus,encephalomyocarditis virus, Colorado tick fever virus, Cowpox virus,Eastern equine encephalitis virus, Venezuelan equine encephalitis virus,Argentine hemorrhagic fever virus, Bolivian hemorrhagic fever virus,Lacrosse virus, Hantaan virus, JC virus, Lassa virus, Lymphocyticchoriomeningitis virus, Kyasanur forest virus, Marburg virus, Measlesvirus, Mokola virus, Monkeypox virus, Molluscum contagiosum virus, Mumpsvirus, Murray Valley encephalitis virus, Norwalk virus, O'nyong-nyongvirus, Omsk hemmorhagic virus, Orf virus, Rabies virus, RA-1 virus,Western equine encephalitis virus, Japanese encephalitis virus, YellowFever Virus, West Nile virus, Variola (smallpox) virus, cowpox virus,Vaccinia virus, Ebola virus, Respiratory syncytial virus, humancytomegalovirus, Rhinoviruses 1-113, Rift Valley fever virus, Ros rivervirus, Rubella virus, Russian spring-summer encephalitis virus, Sandflyfever viruses, St. Louis encephalitis virus, SV40 virus, vaccinia virus,Varicella-zoster virus, Vesicular stomatitis viruses and Bovine ViralDiarrhea Virus. These and other exemplary viruses have been described.See, for example B. N. Fields, et al., editors, Fundamental Virology,3^(rd) edition, 1996, Lippencott-Raven Publishers, see chapter 2 atpages 23-57, including table 4 at pages 26-27, table 5 at pages 28-29,chapter 17 at pages 523-539, chapters 26-27 at pages 763-916, chapter 32at pages 1043-1108 and chapter 35 at pages 1199-1233, T. G. Ksiazek etal., New Engl. J. Med., electronic publication on Apr. 10, 2003 atwww.nejm.org.

In related embodiments, the F1Cs are used to treat, prevent orameliorate Arbovirus infections, Arenavirus infections, Hantavirusinfections and hemorrhagic fever virus infections, or a symptom(s) orcomplication(s) thereof, in subjects such as humans. In these infectionsthe F1Cs can treat, prevent or ameliorate one or more symptoms includingfever, headache, drowsiness, vomiting, stiff neck, mental confusion,muscle trembling, convulsions, and coma. Hemorrhagic fevers in humansare associated with infection by Hantaviruses and Filoviruses such asEbola and Marburg viruses, which can cause infections that includeKorean, Bolivian and Argentinean hemorrhagic fevers, Congo fever andLassa fever.

Hantavirus infection is a viral disease that rodents can transmit tohumans and the infection is associated with serious lung or kidneyinfection. Symptoms of Hantavirus infection of the lungs include one ormore of fever, muscle pain, myalgia, headache, abdominal pain,conjunctival bleeding, diarrhea, or coughing. Hantavirus kidneyinfection may be mild or severe and is associated with fever, headache,backache, abdominal pain, small bruise-like patches on the whites of theeyes, abdominal rash, impaired kidney function, nausea, loss ofappetite, fatigue and intracranial bleeding.

The F1Cs can also be used to treat, prevent or ameliorate infectionscaused by members of the Poxyiridae family, e.g., members of theOrthopoxvirus genus in subjects such as mammals or humans. The compoundscan be used to treat, ameliorate or prevent one or more symptomsassociated with Orthopoxvirus infections. For example, the variola orsmallpox virus causes a serious infection with symptoms that includefever, chills, backache, headache, skin lesions and death. In treatingOrthopoxvirus infections such as a variola infection, the F1Cs canresult in enhanced efficacy of host factors such as cytokines orinterferons such as IFN-α or IFN-γ. The subject may also be optionallytreated with another agent such as IFN-γ, a nucleoside analog or anucleotide analog such as one described herein or in the citedreferences. Treatment of a subject such as a human who is anticipated topotentially come in contact with a virus, e.g., an Orthopoxvirus such asthe variola virus or the vaccinia virus is accomplished by administeringa F1C to the subject by, e.g., daily or intermittent dosing, beginningat about 1-14 days before an anticipated potential exposure.

Parasites that can be treated using a F1C(s) include malaria parasites,sleeping sickness parasites and parasites associated withgastrointestinal infections. Exemplary parasite, fungi, yeast andbacterial infections that can be treated, prevented or ameliorated insubjects such as mammals or humans, include ones caused by or associatedwith species, groups, genotypes, serotypes, strains, genomovars orisolates of gastrointestinal helminths, microsporidia, isospora,cryptococci, cryptosporidia (Cryptosporidium parvum), Trypanosoma sp.(e.g., T. brucei, T. gambiense, T. cruzi, T. evansi), Leishmania sp.(e.g., L. donovani, L. major, L. braziliensis), Plasmodium sp. (e.g., P.falciparum, P. knowlesi, P. vivax, P. berghei, P. yoelli), Ehrlichia sp.(e.g., E. canis, E. chaffeensis, E. phagocytophila, E. equi, E.sennetsu), Entamoeba sp., Babesia microti, Bacillus anthracis, Borreliasp. (e.g., B. burgdorferi), Brucella sp. (e.g., B. militensis, B.abortus), Bartonella sp. (B. henselae), Bordetella sp. (e.g., B.bronchiseptica, B. pertussis), Burkholderia sp., (e.g., B. pseudomallei,B. cepacia), Campylobacter sp., Clostridium sp. (e.g., C. perfringens,C. difficile, C. tetani, C. septicum), Chlamidya sp. (e.g., C.pneumoniae), Francisella sp. (e.g., F. tularensis), Enterococcus sp.(e.g., E. faecalis, E. faecium), Enterobacter sp., Bacteroides sp.(e.g., B. fragilis, B. thetaiomicron), Prevotella sp., Fusobacteriumsp., Porphyromonas sp., Erysipelothrix rhusiopathiae, Escherichia sp.(E. coli), Gardnerella vaginalis, Haemophilus sp. (e.g., H. somnus, H.influenzae, H. parainfluenzae), Klebsiella sp. (K. pneumoniae),Leptospira sp., Legionella pneumonia, Listeria (e.g., L. monocytogenes,L. ivanovii), Morganella sp. (e.g., M. morganii), Mycobacterium sp.(e.g., M. avium, M. bovis, M. Ieprae, M. tuberculosis, M. pneumoniae. M.penetrans), Mycoplasma sp. (e.g., M. fermentans, M. penetrans, M.pneumoniae), Neisseria (e.g., N. gonorrhoeae, N. meningitidis), Nocardiaasteroides, Proteus sp. (e.g., P. mirabilis, P. vulgaris, P.myxofaciens), Providencia sp. (e.g., P. rettgeri, P. stuartii),Pseudomonas sp. (P. aeruginosa), Salmonella sp. (e.g., S. typhimurium,S. tyhpi, S. paratyhpi, S. dublin, S. enteritidis, S. schottmuelleri, S.hirschfeldii), Serratia sp., Shigella sp. (e.g., S. flexneri, S. sonnei,S. dysenteriae), Streptococcus sp. (e.g., S. pneumoniae, S. pyogenes, S.faecalis, S. faecium, S. agalactiae, S. mutans, S. sanguis),Staphylococcus sp. (e.g., S. aureus), Rickettsia sp. (e.g., R.rickettsii, R. prowazekii, R. tsutsugamushi), Treponema sp. (e.g., T.pallidum, T. carateum), Vibrio sp. (e.g., V. cholerae, V.parahaemolyticus, V. mimicus), Yersinia sp. (e.g., Y. enterocolitica, Y.pestis), Pneumocystis sp. (e.g., P. carinii), Aspergillus sp. (e.g., A.fumigatus, A. terreus, A. flavus), Candida sp. (e.g., C. albicans, C.krusei, C. tropicalis), Chlamidya sp. (e.g., C. trachomatis),Schistosoma sp. (e.g., S. mansoni, S. japonicum, S. haematobium),Strongyloides stercoralis, Wucheria bancrofti, Brugia sp. (e.g., B.malayi, B. timori), Trichomonas sp., (e.g., T. vaginalis) and Taeniasp., (e.g., T. pedis, T. solium).

Human Aspergillus infections that can be treated include invasiveaspergilliosis, allergic bronchopulmonary aspergillosis, aspergillomaand chronic necrotizing aspergillosis. Bacterial infections that can betreated, prevented or ameliorated thus include infections byintracellular or extracellular gram positive bacteria, gram-negativebacteria, acid fast bacteria, Mycoplasma or rickettsial infections(e.g., a rickettsial spotted fever infection or a rickettsial typhus orscrib typhus infection). Other pathogens that are amenable to F1Ctreatments are as described. See, e.g., J. B. Peter, editor, Use andInterpretation of Laboratory Tests in Infectious Disease, 5^(th)Edition, pages 1-309, 1998, Specialty Laboratories, Santa Monica,Calif., ISBN 1-889342-13-0.

For any of the infections disclosed herein, a subject who has theinfection, or is susceptible of developing the infection, e.g., bysuspected or potential exposure to an infectious agent, is treated byadministering an effective amount of a F1C to the subject. Such subjectsmay have, or be susceptible to developing another condition, e.g., anautoimmune condition, inflammation condition, cardiovascular conditionor a cancer or precancer as described herein, such as rheumatoidarthritis, systemic lupus erythematosis, Crohn's disease, ulcerativecolitis, type 1 diabetes, type 2 diabetes, peptic ulcers, skin ulcers,oral cavity ulcers, asthma, multiple sclerosis, coronary artery disease,acute or chronic rheumatuc heart disease, atherosclerosis, stroke orlung cancer, that can be related to or exacerbated by the infection. Inthese embodiments, the F1Cs can function by one or more mechanisms,including enhancing innate immune responses, modulating, e.g.,detectably increase or decrease, the level or activity of one or more ofthe transcription factors, enzymes or other biomolecules describedherein, e.g., IL-1α, IL-1β, TNFα, TNF-β, IL-6, IL-8, IL-10, gro-α,IFN-γ, IFN-α, MCP-1, MIP-1α, MIP-1β, MIP-2, IP-10, LT-β, GM-CSF, RANTESor their isotypes or homologs or cortisol. For example, molecules suchas IL1α, TNFα, MIP-1α or MCP-1 are generally decreased in infectionswhere there is an overexpression of one or more of these molecules. Adetectable decrease of one or more of these molecules often occurs.

In an exemplary embodiment, a subject such as a human that is known orsuspected of having been exposed to B. anthracis spores or cells istreated with a F1C. The subject may have overt symptoms of eithercutaneous or pulmonary infection. The F1C is administered at a dosagedisclosed herein, e.g., about 0.05-10 mg/kg/day or about 0.1-5 mg/kg/dayby buccal delivery or by a parenteral route such as subcutaneous,intramuscular or intravenous injection, for about 5-14 consecutive days.An oral dosage would be about 10-25 mg/kg/day of a F1C for about 5-14consecutive days. Dosing with the F1C will typically begin at about thetime that the infection is suspected or is diagnosed, or shortlythereafter, e.g., within about 1-12 hours.

During or after treatment, the patient is optionally monitored and theamelioration of one or more symptoms or a slowed disease progression isobserved. Such symptoms can include one or more of a red-brown bump withswelling at the edges, blisters, formation of a black scab or eschar atthe site of skin infection and edema. Symptoms of cutaneous anthrax thatcan be ameliorated include fever, headache, muscle ache, nausea, andvomiting. In treating B. anthracis infections, the F1Cs will typicallydecrease tissue damage associated with inflammation, enhance innateimmune responses, enhance humoral immune responses, reduce TNFα, IL-1αor IL-1β levels or activity or enhance killing or phagocytosis ofpathogen in the infected subject or the subject's immune cells, e.g.,monocytes, neutrophils or macrophages.

For a pulmonary anthrax infection, amelioration of one or more of fever,bleeding and necrosis of lymph nodes near the lung, local chestinfection, shock, coma or death can occur. Infection of the brain andmeningoencephalitis may occur and is treated in a similar manner,although an increased dosage can be utilized, e.g., about 20-50mg/kg/day of the F1C is administered by a parenteral, e.g., intravenous,sublingual or buccal route. In any of these skin, pulmonary orgastrointestinal infections, the subject is also optionally treatedusing one or more standard antibiotics and routes of administration,e.g., procaine penicillin G, of streptomycin, tetracycline,erythromycin, ciprofloxacin, doxycycline, levofloxacin, norfloxacin oroxofloxacin.

The use of the F1Cs will generally ameliorate the inflammation, sepsisor shock that can occur when antibiotics are administered to subjectshaving a systemic or pulmonary B. anthracis infection. A potentialadverse effect of antibiotic use to treat a systemic or pulmonary B.anthracis infection is serious or potentially lethal inflammation,sepsis and/or shock that results from release of anthrax lethal toxin orfactor or other inflammatory molecules on lysis of the bacteria. Releaseof bacterial lethal factor from lysed bacterial cells is associated withan intense inflammation, which is at least partially mediated by one ormore inflammatory factors such as TNFα, IL-1β, IL-1α, IL-6, IL-8 orCOX-2. The F1Cs detectably reduce the level and/or biological effects ofsuch inflammatory factors and can also detectably maintain or facilitatemacrophage viability or one or more desired macrophage function(s) atthe same time.

Similarly, the F1Cs can be used to treat, prevent or ameliorate aninfection by one or more gram-negative bacteria, e.g., gram-negativeenteric bacteria. Such bacteria are commonly members of the Bartonella,Brucella, Campylobacter, Enterobacter, Escherichia, Francisella,Klebsiella, Morganella, Proteus, Providencia, Pseudomonas, Salmonella,Serratia, Vibrio or Yersinia genera. Use of F1C can reduce the adverseeffects of bacterial lipopolysaccharide or endotoxin that is associatedwith these organisms. For example, the F1Cs are therapeutically usefulfor infection by Yersinia pestis, which causes plague. Several forms ofplague can exist, i.e., bubonic, pneumonic, septicemic, or pestis minor.The compounds ameliorate one or more of the symptoms associated withthese infections. For example, in a bubonic plague infection, symptomstypically arise several days after exposure to Y. pestis, and caninclude a fever of up to 106° F., chills, rapid weak heartbeat, lowblood pressure, lymph node swelling accompanied by tenderness,restlessness, confusion, uncoordinated movements, liver and spleenswelling. Symptoms associated with pneumonic plague include high fever,chills, rapid heartbeat, severe headache, coughing, blood-tinged sputumand rapid and labored breathing.

In septicemic or pneumonic Y. pestis infections, the subject isoptionally treated using one or more standard antibiotics and routes ofadministration, e.g., streptomycin, tetracycline, gentamycin orchloramphenicol according to standard doses and dosing routes.

In a subject having a V. cholerae infection, symptoms typically ariseseveral days after exposure to the pathogen, and can include a fever,chills, diarrhea, which can be serious or fatal if untreated, oliguria,muscle cramps and hypovolemia. In V. cholerae infections, the subject istreated with a F1C and optionally with one or more standard therapies,e.g., intravenous and/or oral replacement of water, glucose andelectrolytes, tetracycline, doxycycline, erythromycin, furazolidonenorfloxacin, trimethoprim and/or sulfamethoxazole, according to standarddosages and routes of administration.

In any of these bacterial infections, the subject is optionally treatedwith a suitable or appropriate antibacterial agent(s). Such agentsinclude one, two or more antibacterial agents selected from anaminoglycoside, an amphenicol, an ansamycin, a H lactam, a lincosamide,a macrolide, a peptide, a tetracycline, a 2,4-diaminopyrimidine, anitrofuran, a quinolone, a sulfonamide, a sulfone, cycloserine,mupirocin and tuberin. Aminoglycosides include dihdrostreptomycin,gentamicin, kanamycin, neomycin, and streptomycin and the amphenicolsinclude chloramphenicol and chloramphenicol palmitate. β-Lactams includecefadroxil, cefamandole, cefatrizine, cefazedone, cefazolin, cefixime,ceftibuten, ceftizoxime, cefuroxime, cephalexin, cephalosporin,cephalothin, amoxicillin, carbenicillin and a penicillin G. Macrolidesor other abtibiotics include clarithromycin, erythromycin, tetracycline,doxycycline, ciprofloxacin and dapsone.

Symptoms and conditions associated with infections that the F1C cantreat include one or more of sepsis, septicemia, fever, e.g., moderateto high fever, inflammation, pain, e.g., chest pain, muscle pain, jointpain, back pain or headache, chills, itching, rash, skin lesions,erythema, e.g., peripheral erythema, lymphadenopathy, e.g., local,regional or systemic lymphadenopathy, nausea, vomiting, cyanosis, shock,coma, necrosis, hemorrhage, encephalitis, meningoencephalitis, cramping,mild to severe diarrhea, cough, weakness, splenomegaly, anorexia andweight loss. Other symptoms that can be treated are known. See, e.g.,The Merck Manual, 17^(th) edition, M. H. Beers and R. Berkow editors,1999, Merck Research Laboratories, Whitehouse Station, N.J., ISBN0911910-10-7, J. B. Peter, editor, Use and Interpretation of LaboratoryTests in Infectious Disease, 5^(th) Edition, pages 1-309, 1998,Specialty Laboratories, Santa Monica, Calif., ISBN 1-889342-13-0.

The F1Cs can reduce rate or severity of coinfection and/or the rate ofprogression of an opportunistic or a latent infection in subjects havinga retrovirus infection. In this embodiment of the invention, subjectssuch as humans infected with HIV1 or HIV2 are treated continuously orintermittently over a period of about 100-180 days. After treatment forthis period of time, the rate of occurrence of new opportunisticinfections is reduced or the rate of progression or re-occurrence of apre-existing opportunistic or latent infection is reduced. Suchopportunistic and latent infections can be one or more of e.g., asymptomatic infection by HSV-1, HSV-2, HHV-6, HHV-8, CMV, HCV, HBV, anoral bacterium, a human papillomavoirus such as HPV type 16, aMycobacterium, Pneumocystis carinii, Candida, Cryptosporidium,Toxoplasma, Cryptococcus, Staphylococcus, Salmonella, Plasmodium or acardiac viral, fungal or bacterial infection. The reduced rate of theincidence, severity or progression of opportunistic or latent infectionsis maintained during the time at which the F1C is dosed to the subjectand for a period of time after dosing has ended, e.g., for about 2, 3,4, 5, 6, 7 or 8 weeks after dosing has terminated. In cases where theF1C is administered to the subject by an intermittent dosing method, thetime at which the occurrence of new opportunistic infections oremergence of latent infections is generally reached after 2, 3 or 4rounds of intermittent dosing is completed. Such intermittent dosing cancomprise administering 1-6 daily doses over a 1 week period, e.g., onedose on a single day, 2 consecutive daily doses, 5 consecutive dailydoses or 2, 3 or 4 doses given every other day for a week, followed byno dosing for about 1, 2, 3, 4, 5, 6, 7 or 8 weeks, which is thenfollowed by one or more rounds of dosing and no dosing. Reducedopportunistic and latent infections will be particularly pronounced inpatients who are susceptible to such infections, e.g., humans having aCD4+ T cell count of about 25-100 cells/mm³, but who are not acutely orcritically compromised by the retroviral infection at the time dosingwith the F1C is initiated. Other effects that are observed at this timeinclude decreased levels of pro-inflammatory cytokines and decreasedtissue damage associated with inflammation, e.g., cardiac damage. F1Cssuch as 3α,16α-dihydroxyandrostane-17-one,3β,16α-dihydroxyandrostane-17-one, 3α,17β-dihydroxyandrostane-16-one,3β,17β-dihydroxyandrostane-16-one and 3β,16α,17β-trihydroxyandrostanecan be used in these methods.

For subjects who have a viral or parasite infection and are in thecourse of a F1C treatment, other treatments can also be administered tothe subject, e.g., nucleoside analogs for viral infections or anantimalarial(s) agent such as one or more of artemisinin,dihydroartemisinin, a artemisinin analog (e.g., as disclosed in J. Hanet al., J. Nat. Products 64:2101-1205 2001 or G. A. Balint Pharmacol.Ther. 90:261-265 2001), dapsone, sulfadoxin, pyrimethamine, chloroquine,mefloquine, halofantrine, proguanil, proguanil hydrochloride,cycloguanil, chlorocycloguanil, atovaquone, quinine, berberine, and/orprimaquine for subjects having or subject to developing a malariainfection. Subjects suffering from or subject to developing a fungalinfection can optionally be treated with a F1C and an antifungal agent,e.g., an azole or a polyene such as ketoconazole, fluconazole,anidalfungin, amphotericin B or a liposomal formulation that comprisesan azole or polyene such as amphotericin B. Exemplary antiviral agentssuitable for use in the method include reverse transcriptase orpolymerase inhibitors such as AZT (zidovudine or3′-azido-3′-deoxythymidine), 3TC, D4T, ddI, ddC,2′,3′-dideoxynucleosides such as 2′,3′-didoxycytidine,2′,3′-dideoxyadenosine, 2′,3′-didoxyinosine, 2′,3′-didehydrothymidine,carbovir and acyclic nucleosides, e.g., acyclovir, ganciclovir.Exemplary protease inhibitors, fusion inhibitors or other antiviral orantiretroviral agents that may be used in a combination therapy with aF1C include lamivudine, indinavir, nelfinavir, amprenavir, ritonavir,crixivan, sequanavir, nevirapine, stavudine, a HIV fusion inhibitor,efavirenz, co-trimoxazole, adefovir dipivoxil,9-[2-(R)-[[bis[[(isopropoxy-carbonyl)oxy]-methoxy]phosphinoyl]methoxy]propyl]adenine,(R)-9-[2-(phosphonomethoxy)-propyl]adenine, tenofivir disoproxil and itssalts (including the fumarate salt), TAT inhibitors such as7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2(H)-one or nucleic acidsthat comprise one or more unmethylated CpG sequences essentially asdisclosed in, e.g., U.S. Pat. No. 6,194,388.

The antiviral or antimicrobial agents or treatments in combinationtherapies with a F1C will be or are used essentially according to new orto known dosing and administration methods for those agents ortreatments. Their use may precede, overlap or be coincident in time withor follow a treatment protocol with a F1C. In some embodiments, theother therapeutic agents or treatments will overlap and will thus beadministered on one or more of the same days on which a F1C isadministered to a subject having a viral infection, or subject to aviral infection. In other embodiments, the other therapeutic agents ortreatments will be administered to such a subject within about 1 day toabout 180 days before or after a treatment protocol or a dosing periodwith a F1C begins or ends. In exemplary embodiments, the other suitabletreatment or agent is administered within 1 day, 2 days, 3 days, 4 days,about 7 days, about 14 days, about 28 days or about 60 days before orafter a treatment protocol or a dosing period with a F1C begins or ends.

Although the forgoing combination therapies have been described in thecontext of viral or other infections, the protocols and methods thatemploy a F1C can be used in conjunction with any suitable new or knowntherapeutic agent(s) or treatment protocol(s) for other any otherclinical condition described herein. Any of these additional treatmentscan be coupled with the administration of any of the F1Cs in any of theembodiments described herein. Exemplary conditions include one or moreof a non-viral pathogen infection(s), a cancer(s), a precancer(s), aninflammation condition(s), an autoimmune condition(s), animmunosuppression condition(s), a neurological disorder(s), acardiovascular disorder(s), a neurological disorder(s), diabetes,obesity, wasting, anorexia, anorexia nervosa, a cancer chemotherapy(ies)side-effect(s), a side-effect(s) of a chemotherapy(ies) or a radiationtherapy(ies) of any other clinical condition disclosed herein or in thecited references, or the like. Thus, invention embodiments include theuse of a F1C before, during or after a treatment that uses anothersuitable therapeutic agent(s) or therapeutic treatment(s) for any of thediseases or conditions disclosed herein, any of which diseases orconditions may be acute, chronic, severe, mild, moderate, stable orprogressing.

Examples of such agents, treatments or chemotherapies include the use ofone or more adrenergic agents, adrenocortical suppressants, aldosteroneantagonists, anabolics, analeptics, analgesics, anesthesia,anthelmintics, antiacne agents, anti-adrenergics, anti-allergics,anti-amebics, anti-androgens, antianginals, anti-anxiety agents,anti-arthritics, anti-asthmatic agents, anti-atherosclerotic agents,antibacterials, anticholinergics, anticoagulants, anticonvulsants,antidepressants, antidiabetics, antidiarrheals, antidiuretics,anti-emetics, anti-epileptics, anti-estrogens, antifibrinolytics,antifungals, antihistamines, antihyperlipidemia agents,antihyperlipoproteinemic agents, antihypertensive agents,antihypotensives, anti-infectives, anti-inflammatory agents such asentanercept (a dimeric fusion comprising a portion of the human TNFreceptor linked to the Fc protion of human IgG1 containing the C_(H)2and C_(H)3 domain and hinge regions of IgG1) or a COX-2 inhibitor suchas celexicob(4-5-[-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzenesulfonamide)or rofecoxib (4-[4-methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone),antimalarial agents, antimicrobials, antimigraine agents, antimycoticagents, antinausea agents, antineoplastic agents, antiparasitics,antiparkinsonian agents, antiproliferatives, antiprostatic hypertrophyagents, antiprotozoals, antipruritics, antipsychotics, antirheumatics,antischistosomals (e.g., praziquantel, artemisinin), blood glucoseregulators, bone resorption inhibitors, bronchodilators, cardiacdepressants, cardioprotectants, choleretics, depressants, diuretics,dopaminergic agents, enzyme inhibitors, free oxygen radical scavengers,glucocorticoids, peptide hormones, steroid hormones,hypocholesterolemics, hypoglycemics, hypolipidemics, hypotensives,immunomodulators, liver disorder treatments, mucosal protective agents,nasal decongestants, neuromuscular blocking agents, plasminogenactivators, platelet activating factor antagonists, platelet aggregationinhibitors, post-stroke and post-head trauma treatments, progestins,psychotropics, radioactive agents, relaxants, sclerosing agents,sedatives, sedative-hypnotics, selective adenosine A1 antagonists,serotonin antagonists, serotonin inhibitors, serotonin receptorantagonists, thyroid inhibitors, thyromimetics, tranquilizers,vasoconstrictors, vasodilators, wound healing agents, xanthine oxidaseinhibitors or a treatment(s) or therapeutic agent(s) for amyotrophiclateral sclerosis, ischemia, e.g., cereberal ischemia, cardiac ischemiaor cardiovascular ischemia, or unstable angina. The selection and use ofthese agents for a particular subject will typically use dosing methods,dosages and routes of administration essentially according to knownmethods, dosages and routes of administration. Such methods, dosages androutes of administration are described in detail at, e.g., Textbook ofAutoimmune Diseases, R. G. Lahita, editor, Lippincott Williams & Wikins,Philadelphia, Pa., 2000, ISBN 0-7817-1505-9, pages 81-851, Holland•FreiCancer Medicine ^(e.)5, 5^(th) edition, R. C. Bast et al., editors,2000, ISBN 1-55009-113-1, pages 168-2453, B. C. Becker Inc. Hamilton,Ontario, Canada, Hematology, Basic Principles and Practice, 3rd edition,R. Hoffman, et al., editors, 2000, ISBN 0-443-77954-4, pages 115-2519,Churchill Livingstone, Philadelphia, Pa., Rheumatology, 2^(nd) edition,J. H. Klippel et al., editors, 1998, ISBN 0-7234-2405-5, volume 1,sections 1-5 and volume 2, sections 6-8, Mosby International, London,UK, Alzheimer's Disease and Related Disorders: Etiology, Pathogenesisand Therapeutics, K. Iqbal, et al., editors, 1999, ISBN 0-471986386,John Wiley & Son Ltd, and Cardiovascular Medicine, E. J. Topol, editor,Lippincott Williams & Wikins, Philadelphia, Pa., 1998, ISBN 0781716810.

In some infections, the F1C(s) effects an improvement of one or more ofthe symptoms associated with the infection or a symptom thereof. Forexample, treatment of subjects who are immune suppressed, e.g., from aretrovirus infection, cancer chemotherapy or other cause, generally showimprovement of one or more associated symptoms, such as weight loss,fever, anemia, pain, fatigue or reduced infection symptoms that areassociated with a secondary infection(s), e.g., HSV-1, HSV-2, papilloma,human cytomegalovirus (“CMV”), Pneumocystis (e.g., P. carinii) orCandida (C. albicans, C. krusei, C. tropicalis) infections.

In some embodiments, the F1C(s) is administered as a nonaqueous liquidformulation as described herein or the F1C(s) is administered accordingto any of the intermittent dosing protocols described herein using asolid or liquid formulation(s). In the case of a subject who has aretroviral infection, e.g., a human with an HIV infection, with symptomsthat include one or more of, a relatively low CD4 count (e.g., about10-200, or about 20-100 or about 20-50), one or more additional pathogeninfections (HSV-1, HSV-2, HHV-6, HHV-8, CMV, HCV, a HPV, P. carinii orCandida infection) and one or more of anemia, fatigue, Kaposi's sarcoma,fever or involuntary weight loss (at least about 5% of body weight),administration of about 0.1 to about 10 mg/kg/day (usually about 0.4 toabout 5 mg/kg/day) of a F1C(s) to the subject typically results innoticeable improvement of one or more of the symptoms within about 1-4weeks. In other embodiments, the F1C(s) is administered to a subject whohas a condition that appears to be associated with a viral infection,e.g., pneumonia or retinitis associated with CMV, nasopharyngealcarcinoma or oral hairy leukoplakia associated with Epstein-Barr virus,progressive pancephalitis or diabetes associated with Rubella virus oraplastic crisis in hemolytic anemia associated with Parvovirus 19.

One or more intermittent dosing protocols disclosed herein or one ormore of the liquid non-aqueous formulations described herein can beapplied by routine experimentation to any of the uses or applicationsdescribed herein. For a F1C(s) that is a new compound per se, thecompound(s) can be administered to a subject according to an inventionintermittent dosing protocol(s) or by other protocols, e.g., continuousdaily dosing of a single dose or two or more subdoses per day. Inaddition any of the F1Cs, e.g., one or more F1Cs that are new per se,can be present in any solid or liquid formulation described herein.These formulations and dosing protocols can be applied by routinemethods to any of the uses or applications described herein.

Antibodies, vaccines and vaccine adjuvants. The F1Cs can be used toenhance cellular or humoral responses to vaccination against, e.g.,infectious agents or malignant cells. F1Cs can also be used to makeantibodies that bind to the F1Cs themselves or their metabolic products.Antibodies that bind to the F1Cs can be used, e.g., in diagnostic,quality control, or the like, methods or in assays for the F1Cs or theirmetabolites. In addition, the F1Cs are useful for raising antibodiesagainst otherwise non-immunogenic polypeptides, in that the compoundsmay serve as haptenic sites stimulating an immune response against thepolypeptide.

Immunogens that are used to make antibodies that bind to a F1C comprisea F1C that has 1 or more epitopes and optionally another immunogenicsubstance. The immunogenic substance can be covalently bonded to the F1Cto form an immunogenic conjugate or it can be in a mixture ofnon-covalently bonded materials, or a combination of the above.Immunogenic substances include adjuvants such as Freund's adjuvant,immunogenic proteins such as viral, bacterial, yeast, plant and animalpolypeptides, including keyhole limpet hemocyanin, serum albumin, bovinethyroglobulin or soybean trypsin inhibitor, and immunogenicpolysaccharides. Typically, the F1C having one, two or more epitopes iscovalently conjugated to an immunogenic polypeptide or polysaccharide bythe use of a polyfunctional (ordinarily bifunctional) cross-linkingagent. Methods for the manufacture of immunogens that comprise one ormore haptens are conventional per se. Methods for conjugating haptens toimmunogenic polypeptides or the like are used here. Such conjugates areprepared in conventional fashion. For example, the cross-linking agentsN-hydroxysuccinimide, succinic anhydride or C₂₋₈ alkyl-N═C═N—C₂₋₈ alkylare useful in preparing the conjugates. The conjugates comprise a F1Cthat is attached by a bond or a linking group of 1-100, typically, 1-25,more typically about 1-10 carbon atoms to the immunogenic substance.Typically a polypeptide, polysaccharide or other suitable immunogenicmoiety is conjugated to a site on a F1C in a location that is distantfrom the epitope on the F1C to be recognized. The conjugates areseparated from starting materials and by-products using chromatographyor the like, and then are optionally sterile filtered, or otherwisesterilized, or are optionally vialed for storage. Synthetic methods toprepare hapten-carrier immunogens have been described, see e.g., G. T.Hermanson, Bioconjugate Techniques Academic Press, 1996, pages 419-493.

Animals or mammals are typically immunized once, twice or more timesagainst the immunogenic conjugates that comprise a F1C and an immunogen.Polyclonal antisera or monoclonal antibodies are prepared inconventional fashion. In some embodiments, about 0.0001 mg/kg to about 1mg/kg, e.g., about 0.001 or about 0.01 or about 0.1 mg/kg, ofimmunogenic conjugate or derivative is used on one, two, three or moreoccasions to immunize the subject as described herein. The immunogenicconjugates are administered, orally, topically or parenterally asdescribed herein, e.g., by i.m. or s.c. injection. Methods to prepareantibodies, including methods to obtain antibodies that bind to steroidshave been described, see, e.g., R. O, Neri et al., Endocrinology74:593-598 1964, M. Ferin et al., Endocrinology 85:1070-1078 1969, J.Vaitukaitis et al., J. Clin. Endocr. Metab. 33:988-991 1971 and M. Ferinet al., Endocrinology 94:765-775 1974. Such methods can be usedessentially as described to prepare antibodies or monoclonal antibodiesthat bind to a F1C. Embodiments include serum or other preparations thatcomprise any polyclonal or monoclonal antibodies that bind to a F1C(s),methods to make such antibodies and compounds or compositions that areused in conducting these methods.

In other embodiments the F1Cs are used as adjuvants to enhance asubject's immune response to antigens such as proteins, peptides,polysaccharides, glycoproteins or killed or attenuated viruses or cellpreparations. In these methods, an effective amount of the F1C isadministered at about the same time that the antigen is delivered to thesubject, e.g., within about 1, 2, 3, 4, 5, 6, or 7 days of when theantigen is administered to the subject. In some embodiments, the F1C isadministered 1, 2, 3, 4 or more times (usually once or twice per day) at1, 2, 3 or 4 days before or after the antigen is administered to thesubject. In other embodiments, the F1C is administered on the same daythat the antigen is administered to the subject, e.g., within about 1-4hours. Such immunization methods may be repeated once, twice or more asneeded. The F1C can be administered to the subject using any of theformulations or delivery methods described herein or in the referencescited herein. Subjects suitable for these vaccinations include young andelderly mammals, including humans, e.g., humans about 3-36 months of ageor older and humans about 60, 65, 70, 75 years of age or older. Theamount of antigen used can be about 0.01 μg/kg to about 20 mg/kg,typically about 1-100 μg/kg. Dosages of the F1C used in thesevaccinations is essentially as described herein, e.g., about 5 mg toabout 1000 mg of a F1C is used per day on days when it is administeredas part of the vaccination method.

Related embodiments include compositions or formulations that comprise aF1C, an antigen(s) or antigen(s) preparation and optionally one or moreexcipients. The antigen is essentially as disclosed herein or in a citedreference. Antigen preparations may comprise one or more of (1) lethallyor sublethally radiated cells or pathogens, (2) disrupted cells orviruses or such as attenuated viruses, (3) a nucleic acid or DNAvaccine, (4) an antigenic protein, glycoprotein, polysaccharide or afragment or derivative of any of these molecules, (5) chemically treatedcells or pathogens, e.g., formalin or detergent treated cells, virusesor cell or virus extracts and (6) genetically engineered viral orbacterial vectors that express one or more antigens or antigenfragments. Pathogens include prions or the etiologic agents of, e.g.,Creutzfelt-Jacob disease, bovine spongiform encephalopathy and scrapiein sheep, goats or mice. Where cells or disrupted are present in anantigen preparation, they may by genetically modified, e.g., to expressone or more antigens or epitopes against which an immune response isdesired. Antigens in these embodiments are moieties that can elicit adetectable immune response when it is administered to a subject. In someembodiments, the antigen is foreign to the subject. For foreignantigens, the subject to be vaccinated may not encode or express theantigen, while the antigen is usually part of or expressed by a pathogenor by a subject or mammal of a different species. In other embodiments,antigens are endogenous or non-foreign to the subject, e.g., they areusually encoded or expressed by the subject or another subject of thesame species. Endogenous antigens are suitable for use in, e.g., tumorvaccination methods.

Exemplary tumors from which a suitable antigen(s) may be obtained are asdescribed herein or in the cited references. A DNA vaccine as used heretypically comprises a nucleic acid, usually DNA, that encodes one ormore antigens or epitopes that a pathogen, e.g., a parasite, fungus,virus or bacterium, or a tumor encodes or can express. Tumor antigensthat are suitable for use in vaccination methods that employ a F1Cinclude tumor-associated antigens and tumor-specific antigens. Thesemolecules typically comprise one or more protein, glycoprotein,carbohydrate or glycolipid. Vaccinations that employ a tumor antigen(s)may comprise autologous tumor cells or allogenic tumor cells, which areoptionally disrupted and optionally used with a non-formula 1 adjuvant,such as bacillus Calmette-Guerin (BCG), purified protein derivative,Freund's complete adjuvant, Corynebacterium parvum, Mycobacteriumvaccae, oligonucleotides that consist of or comprise an unmethylated CpGdimer or an alum precipitate. In some embodiments, tumor cells treatedwith neuraminidase comprise all or part of the tumor antigen source. Thenon-formula 1 adjuvants are also optionally used in any of thevaccination methods disclosed herein. As used here, tumor associatedantigens, e.g., the carcinoembryonic antigen, α-fetoprotein or theprostate specific antigen, are molecules that are often associated withor detectably expressed by premalignant or malignant cells or cellpopulations and also with some normal tissues during at least part ofthe subject's life cycle.

Other suitable antigens include STn, sialyl Tn-KLH, carbohydrateconjugates, carcinogenic embryonic antigen, MAGE-1, MUC-1, HER-2/neu,prostate specific antigen, p53, T/Tn, bacterial flagella antigens orcapsular polysaccharide antigens (e.g., Staphylococcus aureus capsularpolysaccharide antigens) and antigenic fragments or antigenic syntheticderivatives of any of these molecules, e.g., a fragment or derivativethat retains at least about 20% or 30% of the antigenicity of the nativeor intact molecule. See, e.g., L. A. Holmberg et al., Bone MarrowTransplant. 2000 25:1233-1241, J. W. Hadden, Int. J. Immunopharmacology1999 21:79-101, G. Ragupathi et al., Glycoconj. J. 1998 15:217-221, A.I. Fattom et al., Infect. Immun. 1998 66:4588-4592, U.S. Pat. Nos.5,770,208, 5,866,140 and 6194161 and citations elsewhere herein,including the preceding paragraph.

An antigenic protein, peptide or glycoprotein can be identified bystandard methods, e.g., protein or nucleic acid sequencing, for any ofthe infectious agents or tumors that are described herein or in thecited references. Thus, in some embodiments, an effective amount of aF1C and an antigen are administered to a subject, or delivered to thesubject's tissues, to stimulate an immune response against the antigen.The antigen may comprise one, two or more antigenic epitopes, which maycome from one, two or more genes. In some embodiments, the subject isoptionally monitored to follow or determine the immune, dendritic cell,B cell, T cell, antibody or cytokine response, such as one disclosedherein, e.g., modulation or increase in γIFN, IL-2 or IL-12 levels ormeasurement of the production of one or more immunoglobulin types orsubtypes. The subject may also be monitored by in vitro cell assays,e.g., for activation of T cells or subsets of T cells or other relevantwhite blood cell types. Such assays include measuring T cell activationusing chromium release assays, or mixed lymphocyte assays. The subjectis optionally treated with one or more additional booster vaccinations,when this is called for under the circumstances.

Nucleic acid or DNA vaccines as used here will typically comprise anucleic acid comprising an expressible region that encodes one, two ormore suitable antigens or epitopes, e.g., all or an antigenic portion ofa viral, bacterial, fungal or parasite protein or glycoprotein. Theexpressible region will usually comprise a transcription promoter andoptionally other control sequences that are operatively linked to theantigen coding region where the promoter and control sequences aretranscriptionally active in the intended subject or tissue. Suitablecontrol sequences include enhancers, recognition sequences fortranscription factors and termination sequences. Such expression vectorsmay optionally comprise one, two or more expressible genes or genefragments, which may each comprise their attendant operatively linkedexpression sequences. Suitable methods and expression vectors to delivernucleic acids for vaccine purposes have been described, e.g., U.S. Pat.Nos. 5,223,263, 5,580,859, 5,703,055, 5,846,946 and 5910488.

Vaccinations that utilize a F1C and an antigen(s) are generally suitablefor eliciting or enhancing desired immune responses in conjunction withexposure of a subject to an antigen(s), compared to vaccination withoutthe compound. Antigen specific humoral antibody responses or antigenspecific T cell responses may be enhanced or elicited. Typicallyvaccination using a F1C and a suitable antigen is conducted to prevent apotential infection or to reduce the severity of a future infection.However, in some cases the vaccination is conducted in a subject thathas an infection such as a chronic or a latent infection such as aparasite or a retrovirus or herpesvirus infection, which may be latentor in relapse. In other cases the subject may have a cancer orprecancer. Thus, the subject may be exposed to, or contain, one or moreof the antigens that are used in one of these vaccination procedures.Such vaccinations are included within the scope of the invention.

In related embodiments, the F1Cs are useful to facilitate preparation ofhybridoma clones that express monoclonal antibodies. In these methods, asuitable amount of a F1C, e.g., about 100 μg to about 2 mg for a smallmammal, is administered to a subject, e.g., a mouse, to enhance theimmune response to the desired antigen, which is also administered tothe subject. After antigen challenge, suitable cells are recovered fromthe subject, e.g., anti-antigen immunoglobulin expressing HPRT⁺ spleencells from a mouse. These cells are then fused with suitable immortalcells (e.g., mouse melanoma cells) using, e.g., PEG or Sendai virus, andselected in suitable selection growth medium, e.g., tissue culturemedium that contains hypoxanthine, aminopterin and thymidine, to obtaina group or panel of hybridomas that express anti-antigen monoclonalantibodies. The hybridoma panel is used to generate individual clones,which are optionally screened to determine the antibody specificity andantigen binding properties. About one, 100, 1000, 10,000, 100,000 ormore individual clones are screened by standard methods. The monoclonalantibodies may be from any suitable source, e.g., murine, human,human-murine hybrid or the like. Methods to obtain human, human-murinehybrid or related monoclonal antibodies have been described, e.g., U.S.Pat. Nos. 5,562,903, 5,461,760, 5,705,154, 5,854,400, 5,858,728,5,874,082, 5,874,540, 5,877,293, 5,882,644, 5,886,152, 5,889,157,5,891,996, 5,916,771, 5,939,598, 5,985,615, 5,998,209, 6,013,256,6,075,181, 6,901,001, 6,114,143, 6,114,598, 6,117,980. The F1Cs can beused in any of the methods disclosed in these references to facilitategeneration or recovery of hybridoma panels and clones that expressmonoclonal antibodies.

An aspect of these methods comprise a product, i.e., a hybridoma panelor a hybridoma clone, that is obtained by the process of contacting asubject (such as a mouse) with (1) a suitable amount of a F1C and (2) asuitable amount of an antigen, allowing sufficient time to generate animmune response in the subject against the antigen and then fusingsuitable anti-antigen immunoglobulin producing cells from the subject,e.g., the subject's spleen cells, with a suitable immortal cell line(e.g., a HPRT⁺ mouse myeloma). The antigen or immunogen is as describedabove, e.g., a suitable protein, protein fragment or glycoprotein suchas an interleukin, cytokine or antigen from an infectious agent. Inthese methods, a mouse is typically the subject, but other mammals,e.g., humans or other rodents, are also suitable according to knownmethods.

The amount of antigen for immunization used in preparing monoclonalantibodies in a human or a mammal will typically be about 1 μg to about1000 μg, e.g., about 2 μg, 5 μg, 10 μg, 50 μg or 100 μg of antigen. Theantigens are essentially as described in the vaccination methodsdescribed above, e.g., disrupted cell, a protein or glycoprotein, whichis optionally combined with a suitable amount of an adjuvant such asFreund's complete adjuvant, alum precipitate, a bacteriallipopolysaccharide or BCG.

Related embodiments include a method comprising administering to asubject (e.g., a mammal such as a human or a primate), or delivering tothe subject's tissues, an effective amount of a F1C and a specificantigen. Immune responses that are enhanced include a mucosal immuneresponse to an antigen such as a protein, peptide, polysaccharide,microorganism, tumor cell extract or lethally radiated tumor or pathogencells (e.g., antigens or cells from melanoma, renal cell carcinoma,breast cancer, prostate cancer, benign prostatic hyperplasia, virus orbacteria, or other tumor or pathogen as disclosed herein). Aspects ofthese embodiments include enhancement of the subject's immune responsewhen an antigen or immunogen is administered intranasally or orally. Inthese aspects, the F1C is administered about simultaneously with theantigen or within about 3 hours to about 6 days of antigenadministration. The use of immune modulating agents to enhance immuneresponses to a vaccine has been described, e.g., U.S. Pat. No.5,518,725.

Other uses for the F1C(s) include administering the compound(s) to asubject who suffers from a pathological condition(s). The treatment maytreat or ameliorate the source of the condition(s) and/or symptomsassociated with the pathological condition(s) such as infection with apathogen(s) (viruses, bacteria, fungi), a malignancy, unwanted immuneresponse, i.e., an immune response that causes pathology and/orsymptoms, e.g., autoimmune conditions or allergy or conditions such ashypoproliferation conditions, e.g., normal or impaired tissue growth, orwound healing or burn healing, or in immunosuppression conditions, e.g.,conditions characterized by an absence of a desired response and/or aninadequate degree of a desired response.

Enhanced antibody responses include detectable enhancement of antibodytiter or a shift in the antibody, e.g., an antibody response from a Th2biased response to an increased Th1 biased component of the response. Insuch antibody shifts, the Th1 and Th2 character of the response isdetermined by known methods. For example, a relatively low ratio of IgG1(or the analogous antibody subclass in humans and other subjects) toIgG2a (or the analogous antibody subclass in humans and other subjects),e.g., about 6:1 to about 12:1, that is generated after exposure of asubject (a mouse for the IgG1 and IgG2a subclasses) to an antigenindicates a Th1 biased antibody response. Conversely a higher ratio,e.g., about 20:1 to about 30:1 indicates a Th1 biased antibody response.Generation of antigen-specific IgG1 generation involves T-helper type 2(Th2) cells, and for IgG2a, T-helper type 1 (Th1) cells. The F1Cs candetectably increase the Th1 character of an antibody response to anantigen or they can increase the magnitude of both the Th1 and Th2response.

Exemplary pathogens or cells that are suitable sources for antigens or agene(s) that encode suitable antigens include pathogens described hereinor in the cited references.

Cancer and hyrerproliferation conditions. Many cancers, precancers,malignancies or hyperproliferation conditions are associated with anunwanted Th2 immune response, a deficient Th1 response or unwantedinflammation. An insufficient Th1 immune response may play a role in thecapacity of malignant or premalignant cells to escape immunesurveillance. Any of the F1Cs disclosed herein, may thus be used totreat, prevent or slow the progression of one or more cancers,precancers or cell hyperproliferation conditions or they may be used toameliorate one or more symptoms thereof. In these conditions, the F1Csare useful to enhance the subject's Th1 responses or to reestablish amore normal Th1-Th2 balance in the subject's immune responses. The F1Csmay function at least in part by decreasing inflammation or inflammationassociated markers such as IL-6 and/or by enhancing hematopoiesis inmany of these conditions.

These conditions include cancers or precancers comprising carcinomas,sarcomas, adenomas, blastoma, disseminated tumors and solid tumors suchas one associated with or arising from prostate, lung, breast, ovary,skin, stomach, intestine, pancreas, neck, larynx, esophagus, throat,tongue, lip, oral cavity, oral mucosa, salivary gland, testes, liver,parotid, biliary tract, colon, rectum, cervix, uterus, vagina, pelvis,endometrium, kidney, bladder, central nervous system, glial cell,astrocyte, squamous cell, blood, bone marrow, muscle or thyroid cells ortissue. The F1Cs are thus useful to treat, prevent, slow the progressionof, or ameliorate one or more symptoms of a precancer, cancer or relatedhyperproliferation condition such as myelodysplastic syndrome, actinickeratoses, endometriosis, Barrett's esophagus, leiomyoma, fibromyoma,benign or precancerous intestinal or bowel polyps or benign prostatichyperplasia. The compounds can also be used to treat, prevent, slow theprogression of, slow the replication or growth of, or to ameliorate oneor more symptoms of a primary tumor, a metastasis, an advancedmalignancy, a blood born malignancy, a leukemia or a lymphoma. Any ofthese conditions may be in an early or mild form or can be moderate oradvanced in the existent or progression of the disease or a symptom.

In treating endometriosis, the use of an F1C will slow the rate ofdisease progression and decrease the severity or frequency of one ormore symptoms such as irregular menstrual periods, infertility abdominalpain or cramping and pain in the lower back or pelvic area, which mayprecede menstruation or may accompany sexual intercourse or bowelmovements. Beneficial effects from F1C treatment will be mediated inpatients with endometriosis at least partially by increasing thepatient's Th1 immune responses and/or by decreasing anti-endometrialantibodies or aberrent Th2 immune responses. Treatment of emdometriosiscould be accompanied by other suitable treatments, e.g., treatment withone or more of estrogen, progesterone, danazol, follicle stimulatinghormone antagonists, leutinizing hormone antagonists,gonadotropin-releasing hormone antagonists such as nafarelin acetate oranalgesics such as codeine, tylenol or aspirin.

The F1Cs can be used to treat paraneoplastic syndromes or conditionssuch as ones associated with lung or breast cancers that secretecalcitonin or that enhance osteoclast activity. Such conditions includehypercalcemia, Cushing's syndrome, acromegaly and non-islet cell tumorhypoglycemia. The compounds are used to decrease osteoclast activity orother symptoms associated with such conditions.

Hyperproliferation conditions that can be treated include melanoma,Kaposi's sarcoma, leiomyosarcoma, non-small cell lung cancer, small celllung cancer, bronchogenic carcinoma, renal cell cancer or carcinoma,glioma, glioblastoma, pancreatic or gastric adenocarcinoma,gastrointestinal adenocarcinoma, human papillomavirus associatedcervical intraepithelial neoplasia, cervical carcinoma, hepatoma,hepatocellular carcinoma, hepatocellular adenoma, cutaneous T-celllymphoma (mycosis fungoides, Sezary syndrome), colorectal cancer,chronic lymphocytic leukemia, chronic myelogenous leukemia, ALL orfollicular lymphoma, multiple myeloma, carcinomas with p53 mutations,colon cancer, cardiac tumors, adrenal tumors, pancreatic cancer,retinoblastoma, a small cell lung cancer, a non-small cell lung cancer,intestinal cancer, testicular cancer, stomach cancer, neuroblastoma,neuroma, myxoma, myoma, endothelioma, osteoblastoma, osteoclastoma,osteosarcoma, chondrosarcoma, adenoma, breast cancer, prostate cancer,Kaposi's sarcoma, ovarian cancer, squamous cell carcinoma of thegastrointestinal tract and non-myeloid tumors. Treating a subject with aF1C can ameliorate one or more side effects of chemotherapy or cancersymptoms such as alopecia, pain, fever, malaise, chronic fatigue andcachexia or weight loss. Other cancers, precancers or their symptomsthat can be treated, prevented or ameliorated are described in, e.g.,Holland•Frei Cancer Medicine ^(e.)5, 5^(th) edition, R. C. Bast et al.,editors, 2000, ISBN 1-55009-113-1, pages 168-2453, B. C. Becker Inc.Hamilton, Ontario, Canada or The Merck Manual, 17^(th) edition, M. H.Beers and R. Berkow editors, 1999, Merck Research Laboratories,Whitehouse Station, N.J., ISBN 0911910-10-7.

In some of these embodiments, the subject's hyperproliferation ormalignant condition may be associated with or caused by one or morepathogens. Such conditions include hepatocellular carcinoma associatedwith HCV or HBV, Kaposi's sarcoma associated with HIV-1 or HIV-2, T cellleukemia associated with HTLV I, Burkitt's lymphoma associated withEpstein-Barr virus or papillomas or carcinoma associated with papillomaviruses (e.g., human HPV 6, HPV 11, HPV 16, HPV 18, HPV 31, HPV 45) orgastric adenocarcinoma, gastric MALT lymphoma or gastric inflammationassociated with Helicobacter pylori, lactobacillus, enterobacter,staphylococcus or propionibacteria infection.

In some of these embodiments, the F1Cs may be used to treat, prevent orslow the progression of or ameliorate one or more conditions in asubject having or subject to developing a hyperproliferation conditionwhere angiogenesis contributes to the pathology. Abnormal or unwantedangiogenesis or neovascularization contributes to the development orprogression of solid tumor growth and metastases, as well as toarthritis, some types of eye diseases such as diabetic retinopathy,retinopathy of prematurity, macular degeneration, corneal graftrejection, neovascular glaucoma, rubeosis, retinoblastoma, uvietis andpterygia or abnormal blood vessel growth of the eye, and psoriasis. See,e.g., Moses et al., Biotech. 9:630-634 1991, Folkman et al., N. Engl. J.Med., 333:1757-1763 1995, and Auerbach et al., J. Microvasc. Res.29:401-411 1985.

Dosages of the F1C, routes of administration and the use of combinationtherapies with other standard therapeutic agents or treatments could beapplied essentially as described above for cancer or hyperproliferationconditions or other conditions as disclosed herein. Thus, in someembodiments, the use of the F1C is optionally combined with one, two ormore additional therapies for a cancer or precancer(s), e.g., one, twoor more of surgery and treatment with an antiandrogen or an antiestrogenas described herein or in the cited references, an antineoplastic agentsuch as an alkylating agent, a nitrogen mustard, a nitrosourea, anantimetabolite, a cytotoxic agent, a cytostatic agent, platinum agents,anthracyclines, taxanes or treatment with an analgesic such aspropoxyphene napsylate, acetaminophen, morphine or codeine. Exemplaryanticancer and adjunct agents include tamoxifen, paclitaxel, taxol,docetaxil, methotrexate, vincristine, vinblastine, 5-fluorouracil,thioguanine, mercaptopurine, adriamycin, chlorambucil, cyclophosphamide,cisplatin, carboplatin, transplatinum, irinotecan, procarbazine,hydroxyurea, erythropoietin, G-CSF, bicalutamide, anastrozole,fludarabine phosphate, doxorubicin and any suitable form of any of theseagents, e.g., salts and solvates. Such therapies would be usedessentially according to standard protocols and they would precede, beessentially concurrent with and/or follow treatment with a F1C. In someembodiments, such additional therapies will be administered at the sametime that a F1C is being used or within about 1 day to about 16 weeksbefore or after at least one round of treatment with the F1C iscompleted. In other embodiments, a course of therapy is administered tothe subject, e.g., treatment with a myelosuppressive amount of amyelosuppressive agent such as 5-fluorouracil, cyclophosphamide or aplatinum compound such as cisplatin, followed within about 1, 2, 3, 4, 5or 6 days by administration of one or more courses of treatment with aF1C. Other suitable exemplary therapeutic agents and their use have beendescribed in detail, see, e.g., Physicians Desk Reference 54^(th)edition, 2000, pages 303-3250, ISBN 1-56363-330-2, Medical EconomicsCo., Inc., Montvale, N.J. One or more of these exemplary agents can beused in combination with a F1C to ameliorate, slow the establishment orprogression of, prevent or treat any of the appropriate cancers,precancers or related conditions described herein, or any of theirsymptoms.

In treating cancers or hyperproliferation conditions, the F1Cs maydetectably modulate, e.g., decrease or increase, the expression or levelor activity of one or more biomolecules associated with the prevention,establishment, maintenance or progression of the cancer orhyperproliferation condition. Such biomolecules include one or more ofcarcinoembryonic antigen, prostate specific antigen, her2/neu, Bcl-XL,bcl-2, p53, IL-1α, IL-1β, IL-6, or TNFα, GATA-3, COX-2, NFκB, IkB, anIkB kinase, e.g., IkB kinase-α, IkB kinase-β or IkB kinase-γ, NFAT,calcineurin, calmodulin, a ras protein such as H-ras or K-ras, cyclin D,cyclin E, xanthine oxidase, or their isoforms, orthologs, homologs ormutant forms, which may be observed as either reduced or increasedlevels or biological activity(ies). Biomolecule levels or theiractivity(ies) that can be at least transiently detectably increasedinclude one or more IL-2, IFNγ, IL-12, T-bet,O6-methylguanine-DNA-methyltransferase, calcineurin, calmodulin, asuperoxide dismutase (e.g., Mn, Zn or Cu), a tumor suppressor proteinsuch as the retinoblastoma protein (Rb) or CDKN2A (p16), BRCA1, BRCA2,MeCP2, MBD2, PTEN, NBR1, NBR2 or the isoforms, orthologs, homologs ormutant forms, which may have either attenuated or enhanced biologicalactivity(ies), of any of these molecules. In treating a cancer describedherein such as prostate cancer, one or more of ELAC2,2′,5′-oligoadenylate dependent RNAse L (RNASEL), macrophage scavengerreceptor 1 (MSR1), BRCA2 can be modulated or decreased.

The F1Cs can modulate the synthesis or a biological activity of one ormore other gene products such as transcription factors, enzymes orsteroid or other receptors that are associated with the establishment,progression or maintenance of a cancer or precancer or associatedsymptom. The compounds can inhibit AIB-1 coactivator or HER2/neusynthesis or activity in breast cancer cells or breast cancerconditions. They can enhance the synthesis or an activity of an estrogenreceptor such as ERα, ERβ1 or ERβ2 or progesterone receptor in breastcancer or colon cancer cells or conditions. These effects can includemodulation of the expression or one or more biological activities ofproteins or enzymes that contribute to disease establishment orprogression. Thus, the compounds can decrease IL-4, IL-6 or IL-13expression by stromal cells or immune cells that are in proximity to oradjacent to solid or diffuse tumor cells in a subject such as a human oranother mammal. In the cancers or precancers described herein, thecompounds can thus directly or indirectly modulate (e.g., decrease) theactivity or expression of relevant enzymes such as STAT-6, neutralendopeptidase, a hydroxysteroid dehydrogenase, such as a17β-hydroxysteroid dehydrogenase, 11β-hydroxysteroid dehydrogenase,7β-hydroxysteroid dehydrogenase or a 3β-hydroxysteroid dehydrogenase.

In some embodiments, the F1Cs are used to treat tumors or cancerswherein proliferation of the tumor or cancer cells is enhanced inresponse to sex steroids such as natural or synthetic androgens orestrogens. In other embodiments, the tumor or cancer cells are notresponsive to such hormones or they are only slightly responsive to thepresence of such compounds.

Cardiovascular applications. Any of the F1Cs disclosed herein, may beused to treat, prevent or slow the progression of one or more ofcongenital heart defects, cardiovascular diseases, disorders,abnormalities and/or conditions, or to ameliorate one or more symptomsthereof in a subject. These include peripheral artery disease,arterio-arterial fistula, arteriovenous fistula, cerebral arteriovenousmalformations, aortic coarctation, cor triatum, coronary vesselanomalies, patent ductus arteriosus, Ebstein's anomaly, hypoplastic leftheart syndrome, levocardia, transposition of great vessels, doubleoutlet right ventricle, tricuspid atresia, persistent truncusarteriosus, and heart septal defects, such as aortopulmonary septaldefect, endocardial cushion defects, Lutembacher's Syndrome, ventricularheart septal defects, cardiac tamponade, endocarditis (includingbacterial), heart aneurysm, cardiac arrest, congestive heart failure,congestive cardiomyopathy, paroxysmal dyspnea, cardiac edema,post-infarction heart rupture, ventricular septal rupture, heart valvediseases, myocardial diseases, pericardial effusion, pericarditis(including constrictive and tuberculous), pneumopericardium,postpericardiotomy syndrome, pulmonary heart disease, rheumatic heartdisease, ventricular dysfunction, hyperemia, cardiovascular pregnancycomplications, cardiovascular syphilis, cardiovascular tuberculosis,arrhythmias such as sinus arrhythmia, atrial fibrillation, atrialflutter, bradycardia, extrasystole, Adams-Stokes Syndrome, bundle-branchblock, sinoatrial block, long QT syndrome, parasystole, sick sinussyndrome, ventricular fibrillations, tachycardias such as paroxysmaltachycardia, supraventricular tachycardia, accelerated idioventricularrhythm, atrioventricular nodal reentry tachycardia, ectopic atrialtachycardia, ectopic junctional tachycardia, sinoatrial nodal reentrytachycardia, sinus tachycardia, Torsades de Pointes, and ventriculartachycardia and heart valve diseases such as aortic valve insufficiency,aortic valve stenosis, hear murmurs, aortic valve prolapse, mitral valveprolapse, tricuspid valve prolapse, mitral valve insufficiency, mitralvalve stenosis, pulmonary atresia, pulmonary valve insufficiency,pulmonary valve stenosis, tricuspid atresia, tricuspid valveinsufficiency, and tricuspid valve stenosis.

The F1Cs can be used to treat, prevent or ameliorate one or moresymptoms of myocardial diseases or pathological myocardial or vascularconditions such as alcoholic cardiomyopathy, congestive cardiomyopathy,hypertrophic cardiomyopathy, aortic subvalvular stenosis, pulmonarysubvalvular stenosis, restrictive cardiomyopathy, Chagas cardiomyopathy,endocardial fibroelastosis, myocardial fibrosis, endomyocardialfibrosis, Kearns Syndrome, myocardial reperfusion injury, myocarditis,cardiovascular or vascular diseases such as dissecting aneurysms, falseaneurysms, infected aneurysms, ruptured aneurysms, aortic aneurysms,cerebral aneurysms, coronary aneurysms, heart aneurysms, and iliacaneurysms, angiodysplasia, angiomatosis, bacillary angiomatosis,Sturge-Weber Syndrome, angioneurotic edema, aortic diseases, Takayasu'sArteritis, aortitis, Leriche's Syndrome, arterial occlusive diseases,arteritis, enarteritis, polyarteritis nodosa, cerebrovascular diseases,disorders, and/or conditions, diabetic angiopathies, diabeticretinopathy, thrombosis, erythromelalgia, hemorrhoids, hepaticveno-occlusive disease, hypertension, hypotension, idiopathic pulmonaryfibrosis, peripheral vascular diseases, phlebitis, pulmonaryveno-occlusive disease, Raynaud's disease, CREST syndrome, retinal veinocclusion, Scimitar syndrome, superior vena cava syndrome,telangiectasia, atacia telangiectasia, hereditary hemorrhagictelangiectasia, varicocele, varicose veins, varicose ulcer, vasculitis,venous insufficiency and arterial occlusive diseases such asarteriosclerosis, intermittent claudication, carotid stenosis,fibromuscular dysplasias, mesenteric vascular occlusion, Moyamoyadisease retinal artery occlusion, thromboangiitis obliterans oratherosclerosis, any of which may be at an early stage or at a moreadvanced or late stage.

The F1Cs can also be used to treat, prevent or ameliorate one or moresymptoms of cerebrovascular diseases, thrombosis, and/or conditions suchas carotid artery diseases, cerebral amyloid angiopathy, cerebralaneurysm, cerebral anoxia, cerebral arteriosclerosis, cerebralarteriovenous malformation, cerebral artery diseases, cerebral embolismand thrombosis, carotid artery thrombosis, sinus thrombosis,Wallenberg's syndrome, cerebral hemorrhage, epidural hematoma, subduralhematoma, subarachnoid hemorrhage, cerebral infarction, cerebralischemia (including transient), subclavian steal syndrome,periventricular leukomalacia, vascular headache, cluster headache,migraine, vertebrobasilar insufficiency, air embolisms, embolisms suchas cholesterol embolisms, fat embolisms, pulmonary embolisms or amnioticfluid embolism, thromoboembolisms, thrombosis such as coronarythrombosis, hepatic vein thrombosis, retinal vein occlusion, carotidartery thrombosis, sinus thrombosis, Wallenberg's syndrome, andthrombophlebitis.

The F1Cs can also be used to treat, prevent or ameliorate one or moresymptoms of vascular ischemia or myocardial ischemias, vasculitis andcoronary diseases, including angina pectoris, coronary aneurysm,coronary arteriosclerosis, coronary thrombosis, coronary vasospasm,myocardial infarction and myocardial stunning, cerebral ischemia,ischemic colitis, compartment syndromes, anterior compartment syndrome,myocardial ischemia, reperfusion injuries, peripheral limb ischemia,aortitis, arteritis, Behcet's Syndrome, mucocutaneous lymph nodesyndrome, thromboangiitis obliterans, hypersensitivity vasculitis,Schoenlein-Henoch purpura, allergic cutaneous vasculitis, Wegener'sgranulomatosis or metabolic syndrome, which may be accompanied by one,two or more of obesity, insulin resistance, dyslipidemia, hypertensionor other related symptoms or conditions.

Exemplary symptoms that the use of the F1Cs can ameliorate include oneor more of pain such as arm, jaw or chest pain, edema or swelling, highblood pressure, shortness of breath or dyspnea, e.g., on exertion orwhile prone, fatigue or malaise and low cardiac injection fraction. Intreating a cardiovascular condition in a subject or in improving one ormore symptoms thereof, the F1Cs may accomplish one or more of increasingcardiac ejection volume or fraction, decreasing levels of IL-6,decreasing levels of C reactive protein, fibrinogen, cardiac creatininekinase, increasing fatty acid metabolism or utilization by cardiactissue, increasing carnityl palmitoyl fatty acid transferase or othercardiac metabolic enzymes, activating potassium dependent calciumchannels, vasodilating or enhancing oxygen delivery to ischemic tissuesor decreasing levels of scarring or plaque formation that occurs, e.g.,after vascular damage. Symptoms associated with a cardiovascularcondition such as ischemia that can be ameliorated also includeacidosis, expression of one or more immediate early genes in, e.g.,glial cells, vascular smooth muscle cells or endothelial cells, neuronalmembrane depolarization and increased neuronal extracellular calcium andglutamate concentration. Other biological effects associated withtreatment using a F1C may also be monitored, e.g., and increase ordecrease of a cell surface antigen, a cytokine or an interleukin asdisclosed herein.

Useful biological effects of the F1Cs in cardiovascular indications suchas myocardial ischemias also include preventing or reducing heart orvascular cell death and subsequent fibrosis. These effects areassociated with a decreased oxidative capacity of heart cells ormyocytes, which is associated with a decreased capacity of the cells tometabolize fatty acids efficiently. The compounds enhance fatty acidmetabolism and ameliorate the deleterious effects of a limited oxidativecapacity.

The F1Cs also can limit inflammation or cell injury that is associatedwith ischemia or oxygen reperfusion after ischemia. Ischemia, which is adetrimental decrease in oxygenated blood delivery to affected cells ortissues, may arise from a cardiovascular condition or event such as aninfarction, or from thermal injury or burns. Ischemia may also arisefrom accidental or surgical trauma. Reperfusion after cells have becomehypoxic for a sufficient period of time can lead to tissue or cellinjury that varies from slight to lethal.

The compounds can reduce cell or tissue injury or death associated withischemia and reperfusion, by, e.g., reducing inflammation or the levelof a molecule associated with inflammation. Thus, levels of aproinflammatory cytokine or molecule such as leukotriene B4, plateletactivating factor or levels of extracellular P-selectin may result fromadministration of a F1C to a subject who may experience reperfusioninjury. Thus, the compounds can reduce injury or death of, e.g., neuron,cardiac, vascular endothelium, myocardial, pulmonary, hepatic or renalcells or tissues. Without wishing to be bound by any theory, thecompounds may act in part by reducing one or more of neutrophilactivation, platelet activation, platelet aggregation, endothelial cellactivation and neutrophil adherence or adhesion to endothelial cells inthese conditions.

The F1Cs are useful to treat autoimmune or metabolic conditions ordisorders, or their symptoms, in subjects such as mammals or humans,that relate to impaired insulin synthesis or use or that relate toabnormal or pathological lipid or cholesterol metabolism or levels. Suchconditions and symptoms include polycystic ovarian syndrome, Type 1diabetes (including Immune-Mediated Diabetes Mellitus and IdiopathicDiabetes Mellitus), Type 2 diabetes (including forms with (1)predominant or profound insulin resistance, (2) predominant insulindeficiency and some insulin resistance, (3) forms intermediate betweenthese), obesity, hyperglycemia and dyslipidemia, unwanted hyperlipidemiaconditions such as hypertriglyceridemia and hypercholesterolemias suchas hyper-LDL cholesterolemia, (4) unwanted hypolipidemias, e.g.,hypo-HDL cholesterolemia or low HDL cholesterol levels and (5) anginapectoris. In diabetes, the compounds are useful to (1) enhance β-cellfunction in the islets of Langerhans (e.g., increase insulin secretion),(2) reduce the rate of islet cell damage, (3) increase insulin receptorlevels or activity to increase cell sensitivity to insulin and/or (4)modulate glucocorticoid receptor activity to decrease insulin resistancein cells that are insulin resistant. The compounds are thus useful totreat, prevent, ameliorate or slow the progression of a metabolic orcardiovascular condition such as diabetes or hyperglycemia, or a relatedsymptom or condition such as a dyslipidemia in a subject such as a humanor a mammal.

Beneficial effects that can the F1Cs can exert on such related symptomsor conditions include improved glucose tolerance, improved glucoseutilization, decreased severity or slowed progression of vasculardisease (e.g., microvascular or macrovascular disease, includingnephropathy, neuropathy, retinopathy, hypertension, cerebrovasculardisease and coronary heart disease) or a decreased severity or slowedprogression of atherosclerosis, an arteriosclerosis condition (e.g.,coronary arteriosclerosis, hyperplastic arteriosclerosis, peripheralarteriosclerosis or hypertensive arteriosclerosis), decreased severityor slowed progression of diabetic osteoarthropathy, skin lesions,rhabdomyolysis, ketosis, detectably decreased generation of islet cellautoantibodies, decreased levels or activity of inflammatory macrophages(foam cells) in atherosclerotic plaques, or detectably decreasedexpression or levels of one or more of human (or mammalian)angiopoietin-like 3 gene product, apolipoprotein C-1, inducible orconstitutive nitric oxide synthase, e.g., in endothelial cells,macrophages or the like, pyruvate dehydrogenase kinase 4, carboxyl esterlipase, cholesteryl ester transfer protein, endothelial lipase, vascularwall lipoprotein lipase, anti-lipoprotein lipase autoantibodies,triglyceride-rich lipoproteins, LDL cholesterol, C-reactive protein,high sensitivity C-reactive protein, fibrinogen, plasma homocysteine,VCAM-1, IL-1 (e.g., IL-1β), IL-6, a TNF (e.g., TNFα), AP-1, NF-κB, andIFN-γ. In these any of these diseases or conditions, the F1Cs can alsomodulate, e.g., detectably increase, the activity or level of one, twoor more of human (or mammalian) LOX-1, apolipoprotein A-1,apolipoprotein A-2, LPDL lipase, hormone sensitive lipase, paraoxonase,brain natriuretic peptide, a brain natriuretic peptide receptor, e.g.,Npr1 or Npr3, hepatic lipase, LDL receptor, HDL apoliporpotein E, HDLapoliporpotein J, HDL cholesterol, VLDL receptor, ATP-binding cassettetransporter 1, leukemia inhibitory factor, CD36, LXRα, LXRβ, CARβ, RXR,PPARα, PPARβ, PPARγ or a lipoprotein lipase, e.g., marophage lipoproteinlipase. As used herein, obesity includes a human with a body mass indexof at least about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 orgreater. Obese humans that are treated with a F1C may have one or moreof the conditions described here.

The F1Cs are useful in treating insulin resistance and associatedsymptoms and conditions. Insulin resistance is typically observed as adiminished ability of insulin to exert its biological action across abroad range of concentrations. This leads to less than the expectedbiologic effect for a given level of insulin. Insulin resistant subjectsor human have a diminished ability to properly metabolize glucose orfatty acids and respond poorly, if at all, to insulin therapy.Manifestations of insulin resistance include insufficient insulinactivation of glucose uptake, oxidation and storage in muscle andinadequate insulin repression of lipolysis in adipose tissue and ofglucose production and secretion in liver. Insulin resistance can causeor contribute to polycystic ovarian syndrome, impaired glucosetolerance, gestational diabetes, hypertension, obesity, atherosclerosisand a variety of other disorders. Insulin resistant individuals canprogress to a diabetic state. The compounds can also be used in thetreatment or amelioration of one or more condition associated withinsulin resistance or glucose intolerance including an increase inplasma triglycerides and a decrease in high-density lipoproteincholesterol, high blood pressure, hyperuricemia, smaller denserlow-density lipoprotein particles, and higher circulating levels ofplasminogen activator inhibitor-1. Such diseases and symptoms have beendescribed, see, e.g., G. M. Reaven, J. Basic Clin. Phys. Pharm. 1998, 9:387-406, G. M. Reaven, Physiol. Rev. 1995, 75: 473-486 and J. Flier, J.Ann. Rev. Med. 1983, 34:145-60.

The compounds can thus be used in diabetes, obesity, hyperlipidemia orhypercholesterolemia conditions to reduce body fat mass, increase musclemass or to lower one or more of serum or blood low density lipoprotein,triglyceride, cholesterol, apolipoprotein B, free fatty acid or very lowdensity lipoprotein compared to a subject that would otherwise beconsidered normal for one or more of these characteristics. Thesebeneficial effects are typically obtained with little or no effect onserum or blood high density lipoprotein levels. The F1Cs are useful toreduce or slow the rate of myocardial tissue or myocyte damage, e.g.,fibrosis, or to enhance cardiac fatty acid metabolism in conditions,such as inflammation, where fatty acid metabolism is depressed ordecreased. Elevated cholesterol levels are often associated with anumber of other disease states, including coronary artery disease,angina pectoris, carotid artery disease, strokes, cerebralarteriosclerosis, and xanthoma, which the F1Cs can ameliorate or slowthe progression or severity of. Abnormal lipid and cholesterolconditions that can be treated include exogenous hypertriglyceridemia,familial hypercholesterolemia, polygenic hypercholesterolemia, biliarycirrhosis, familial combined hyperlipidemia, dysbetalipoproteinemia,endogenous hypertriglyceridemia, mixed hypertriglyceridemia andhyperlipidemia or hypertriglycidemia secondary to alcohol consumption,diabetic lipemia, nephrosis or drug treatments, e.g., corticosteroid,estrogen, colestipol, cholestyramine or retinoid treatments. Dosages,routes of administration and dosing protocols for the F1Cs areessentially as described herein. Where the condition is chronic, theF1Cs will generally be administered to a subject such as a human for arelatively long time period, e.g., for about 3 months to about 10 yearsor more. Dosages, routes of administration and dosing protocols for theF1Cs are essentially as described herein. Dosing of the compound can bedaily or intermittent using a dosing protocol using dosages as describedherein, e.g., about 0.01 to about 20 mg/kg of a F1C administered to asubject once or twice per day daily or intermittently. The use of theF1Cs can be combined with one, two or more other suitable treatments,e.g., treatment for cessation of smoking, diet control, e.g., caloricrestriction or reduced fat intake, or treatment with fibrates,non-steroidal anti-inflammatory drugs, angiotensin-converting enzymeinhibitors or HMG-CoA reductase inhibitors such as aspirin, clofibrate,fenofibrate, ciprofibrate, gemfibrozil, Simvastatin™, Pravastatin™,Mevastatin™ or Lovastatin™.

The use of any F1C or species in any genus of F1Cs disclosed herein totreat, prevent or ameliorate any of these cardiovascular or metabolicdisorders or symptoms will generally use one or more of the routes ofadministration, dosages and dosing protocols as disclosed herein. Thus,in exemplary embodiments, about 0.5 to about 100 mg/kg or about 1 toabout 25 mg/kg, of the F1C will be administered per day by an oral,buccal, sublingual or parenteral route. Such administration can be,e.g., daily for about 5 to about 60 days in acute conditions or it canbe intermittent for about 3 months to about 2 years or more for chronicconditions. Alternatively, intermittent dosing can be used essentiallyas described herein for acute cardiovascular conditions. In someembodiments, for conditions such as ischemia or trauma, administrationof the F1C is provided before or as soon after the ischemic or traumaticevent as possible, e.g., within about 6 hours of an ischemic ortraumatic event or about 12-24 hours before an anticipated ischemic ortraumatic event. In other embodiments, administration of the F1C can bedelayed for, e.g., about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19,20, 21, 24, 28, 32, 36, 40, 48 or more hours after an ischemic ortraumatic event has occurred and a course of daily or intermittentdosing is initiated at one of these times, or in a range between any ofthese times after the event. Thus, administration of the F1C can beginat about 10-14 hours, at about 11-13 hours or at about 8-16 hours afterthe ischemic or traumatic event.

In another aspect of the invention, the F1Cs can be used to prevent,treat or to reduce the severity of vascular or microvascular occlusionsin human sickle cell diseases (SCD). SCD is heterogenous and includessubgroups with high transcranial velocities, which is a group with anincreased risk of infarctive stroke or cereberal thrombosis. SCD typesalso include sickle cell-β⁺ thalassemia, sickle cell-β^(◯) thalassemia,sickle cell-δβ^(◯) thalassemia and sickle cell-HPFH (hereditary ofpersistent fetal hemoglobin). Another subgroup of SCD patients ischaracterized by the presence of a Plasmodium parasite infection. SCD isusually accompanied by acute vaso-occlusive episodes such asmicrovascular occlusions, ischemia and infarctions that arise fromadhesion of sickle cells and other blood cell types, e.g., platelets orleukocytes, to vascular endothelial cells. Reduced sickle cell adhesionin response to treatment with a F1C and related responses is facilitatedat least in part by decreased production or activity of one or morebiological response mediators such as one, two, three or more ofthrombospondin, von Willebrand factor, epinephrine, C reactive protein,cAMP, basal cell adhesion molecule/Lutheran (BCAM/Lu), P-selectin,L-selectin, E-selectin, VCAM-1, ICAM-1, fibronectin, annexin V, placentagrowth factor, superoxide, CD11a, CD11b, CD11c, CD15, CD18, CD31, CD36,TNFα, NF-κB, IL-1β or IL-6 by endothelial cells or one or more immunecell types as described herein. In treating sickle cell disease, theF1Cs will also increase the activity or levels of one, two or moredesired response mediators including fetal hemoglobin, erythropoietin,heme oxygenase, nitric oxide, PPARα, PPARγ or GM-CSF. The F1Cs will thusameliorate one or more symptoms of sickle cell disease such as anemia,stroke, pain, e.g., chest or abdominal pain, skin ulcers, dyspnea, organdamage, retinopathy or the level of infected red cells inPlasmodium-infected subjects. Treatment of acute SCD episodes or ofchronic SCD with F1Cs can be combined with other suitable therapies,e.g., inhaled nitric oxide, hydroxyurea treatment, anti-adhesionmolecule antibody treatment or analgesic use such as morphine,oxycodone, or codeine. The F1Cs can also be used to reduce cellulardamage from reactive oxygen species associated with hydroxyureatreatment, since the F1Cs will enhance cellular antioxidant capacity.

As is apparent from the foregoing, the use of the F1C is optionallycombined with one or more additional therapies for cardiovascular orrelated disorders, e.g., insulin therapy, vascular surgery, cardiacsurgery, angioplasty, or treatment with andrenergic blockers, coronaryvasodilators, calcium channel blockers, nitrates, angiotensin convertingenzyme inhibitors, anti-hypertensives, anti-inflammatory agents,diuretics, anti-arrhythmia agents, thrombolytic agents, enzymeinhibitors such as hydroxymethylglutaryl CoA reductase inhibitors orxanthine oxidase inhibitors. Exemplary hydroxymethylglutaryl CoAreductase inhibitors include statins such as mevastatin, lovastatin,pravastatin, simvastatin or compounds described in U.S. Pat. Nos.4,346,227, 4,448,979, 4,739,073, 5,169,857, 5,006,530 or 5401746. Othertherapies that can be applied include diet control, dietary calorierestriction or diet modification for subjects who are or who aresusceptible to developing a cardiovascular or related condition such aspulmonary hypertension, diabetes, a dyslipidemia or obesity, e.g.,humans having a body mass index of 27, 28, 29, 30, 31, 32, 33, 34, 35,36 or greater. Diet modifications include limiting or restricting salt,alcohol, caffeine, cigarette, drugs, e.g., opiate, hallucinogen,sedative, narcotic or amphetamine, sugar, refined sugar and/or fat orcholesterol intake, use or abuse. Additional therapies include treatmentwith one or more of digoxin, nitroglycerin, doxazosin mesylate,nifedipine, enalapril maleate, indomethicin, tissue plasminoginactivator, urokinase, acetylsalicylic acid or the like. Any of suchadditional therapies would be used essentially according to standardprotocols and such therapies would precede, be concurrent with or followtreatment with a F1C. In some embodiments, such additional therapieswill be administered at the same time that a F1C is being used or withinabout 1 day to about 16 weeks before or after at least one round oftreatment with the F1C is completed. Other exemplary therapeutic agentsand their use have been described in detail, see, e.g., Physicians DeskReference 54^(th) edition, 2000, pages 303-3251, ISBN 1-56363-330-2,Medical Economics Co., Inc., Montvale, N.J.; Harrison's Principles ofInternal Medicine, 15^(th) edition, 2001, E. Braunwald, et al., editors,McGraw-Hill, New York, N.Y., ISBN 0-07-007272-8, especially chapters231, 241-248 and 258-265 at pages 1309-1318, 1377-1442 and 1491-1526.One or more of these exemplary agents or treatments can be used incombination with a F1C to treat any of the appropriate cardiovascularand related disorders described herein and in the references citedherein.

Respiratory and pulmonary conditions. F1Cs can be used to treat,ameliorate, prevent or slow the progression of a number of pulmonaryconditions or their symptoms such as 1, 2, 3 or more of cystic fibrosis,bronchiectasis, cor pulmonale, pneumonia, lung abcess, acute bronchitis,chronic bronchitis, chronic obstructive pulmonary diseases, emphysema,pneumonitis, e.g., hypersensitivity pneumonitis or pneumonitisassociated with radiation exposure, alveolar lung diseases andinterstitial lung diseases, e.g., associated with asbestos, fumes or gasexposure, aspiration pneumonia, pulmonary hemorrhage syndromes,amyloidosis, connective tissue diseases, systemic sclerosis, ankylosingspondylitis, allergic granulomatosis, granulomatous vasculitides,asthma, e.g., acute asthma, chronic asthma, atopic asthma, allergicasthma or idiosyncratic asthma, cystic fibrosis and associatedconditions, e.g., allergic bronchopulmonary aspergillosis, chronicsinusitis, pancreatic insufficiency, inflammation or Haemophilusinfluenzae, S. aureus or Pseudomonas aeruginosa infection. In some ofthese conditions where inflammation plays a role in the pathology of thecondition, the F1Cs can ameliorate or slow the progression of thecondition by reducing damage from inflammation. In other cases, the F1Csact to limit pathogen replication or pathogen-associated lung tissuedamage.

For these conditions, the severity of the disease or the type orseverity of associated symptoms can vary. For example, in humans havingpediatric, e.g., infants or children of about 1 month or about 4 monthsof age to about 16 or 17 years of age, or adult cystic fibrosis (“CF”),the disease may be associated with the presence of one or more symptoms,syndromes, genetic mutations or the like. Symptoms or syndromes that canbe observed in human CF patients include 1, 2, 3, 4 or more ofStaphylococcus (e.g., S. aureus), Haemophilus influenzae, Pseudomonas orBurkholderia respiratory tract or lung infection or propensity todevelop detectable infection or colonization, coughing, wheezing,cyanosis, bronchiolitis, bronchospasm, pneumothorax, hemoptysis,pancreatic exocrine insufficiency, bronchiectatic lung disease,atelectasis-consolidation, pulmonary edema, increased lung vascularhydrostatic pressure, increased lung vascular permeability, sinusitis,respiratory insufficiency, bronchial wall or interlobular septathickening, reduction of forced expiratory volume in 1 second, dyspnea,impaired male fertility, elevated sweat chloride (e.g., >60 mmol/L),mucous plugging, tree-in-bud sign, mosaic perfusion pattern, glucoseintolerance or abnormal elevation of one or more of IL-4, IL-8, RANTES,neutrophil elastase, eosinophils, macrophages, neutrophils, eosinophilcationic protein or cysteinyl leukotrienes. Any of these symptoms orsyndromes can be acute, intermittent or chronic and/or mild, moderate orsevere. Relevant mutations include, e.g., a homozygous or heterozygous,dominant or recessive deletion, insertion and/or point mutation in (1)the cationic trypsinogen gene or (2) the cystic fibrosis transmembraneconductance regulator (CFTR) gene, such as one, two or more of, a CFTRF508del deletion mutation or CFTR lacking phe508, 3272-26A>G/F508del,3659delC, 394delTT, S1455X or Δ26, I1234V, 2183AA>G, 2043delG, 548A>T,I148T, R334W, S1196X, 4041C>G, 1161delC, 1756G>T or 3120+1G>A mutation.

The use of a F1C to treat, ameliorate or slow the progression ofconditions such as CF can be optionally combined with other suitabletreatments. For CF, this includes, e.g., one, two or more of oral oraerosol corticosteroid treatment, ibuprofen treatment, DNAse or IL-10treatment, diet control, e.g., vitamin E supplementation, vaccinationagainst pathogens, e.g., Haemophilus influenzae, or chest physicaltherapy, e.g., chest drainage or percussion.

Humans or other subjects who have one or more of these conditions can betreated with other suitable therapeutics. Pulmonary conditions that canbe treated with the F1Cs and other therapeutic methods and agents thatcan be used in conjunction with the F1Cs have been described in detail,see, e.g., Harrison's Principles of Internal Medicine, 15^(th) edition,2001, E. Braunwald, et al., editors, McGraw-Hill, New York, N.Y., ISBN0-07-007272-8, especially chapters 252-265 at pages 1456-1526;Physicians Desk Reference 54^(th) edition, 2000, pages 303-3251, ISBN1-56363-330-2, Medical Economics Co., Inc., Montvale, N.J. One or moreof these exemplary agents or treatments can be used in combination witha F1C to treat any of the appropriate cardiovascular and relateddisorders described herein and in the references cited herein. Treatmentof any of these respiratory and pulmonary conditions using a F1C isaccomplished using the treatment regimens described herein. For chronicconditions, intermittent dosing of the F1C can be used to reduce thefrequency of treatment. Intermittent dosing protocols are as describedherein.

Applications in autoimmunity, allergy, inflammation and relatedconditions. As mentioned above, the F1Cs may be used to treat, preventor slow the progression of one or more autoimmune allergic orinflammatory diseases, disorders, or conditions, or to ameliorate one ormore symptoms thereof in a subject. These diseases and conditionsinclude Addison's Disease, autoimmune hemolytic anemia, autoimmunesensorineural hearing loss, antiphospholipid syndrome, acute or chronicrheumatoid arthritis and other synovial disorders, an osteoarthritisincluding post-traumatic osteoarthritis and hypertrophic pulmonaryosteoarthropathy, psoriatic arthritis, polyarthritis, epichondylitis,type I diabetes, type II diabetes, rheumatic carditis, bursitis,ankylosing spondylitis, multiple sclerosis, a dermatitis such as contactdermatitis, atopic dermatitis, exfoliative dermatitis or seborrheicdermatitis, mycosis fungoides, allergic encephalomyelitis, autoimmuneglomerulonephritis, Goodpasture's Syndrome, Graves' Disease, Hashimoto'sThyroiditis, multiple sclerosis, myasthenia gravis, neuritis, bullouspemphigoid, pemphigus, polyendocrinopathies, purpura, Reiter's Disease,autoimmune thyroiditis, systemic lupus erythematosus, scleroderma,fibromyalgia, chronic fatigue syndrome, autoimmune pulmonaryinflammation, Guillain-Barre Syndrome, type 1 or insulin dependentdiabetes mellitus, autoimmune inflammatory eye disease, hepatitis Cvirus associated autoimmunity, postinfectious autoimmunity associatedwith, e.g., virus or bacterial infection such as a parvovirus such ashuman parvovirus B19 or with rubella virus, autoimmune skin and muscleconditions such as pemphigus vulgaris, pemphigus foliaceus, systemicdermatomyositis or polymyositis or another inflammatory myopathy,myocarditis, asthma such as allergic asthma, allergic encephalomyelitis,allergic rhinitis, a vasculitis condition such as polyarteritis nodosa,giant cell arteritis or systemic necrotizing vasculitis, chronic and anacute or chronic inflammation condition such as chronic prostatitis,granulomatous prostatitis and malacoplakia, ischemia-reperfusion injury,endotoxin exposure, complement-mediated hyperacute rejection, nephritis,cytokine or chemokine induced lung injury, cachexia, sarcoidosis,inflammatory bowel disease, regional enteritis, ulcerative colitis,Crohn's disease, inflammatory bowel disease or inflammation associatedwith an infection, e.g., septic shock, sepsis, or systemic inflammatoryresponse syndrome. Any of these diseases or conditions or their symptomsmay be acute, chronic, mild, moderate, severe, stable or progressingbefore, during or after the time administration of the F1C to a subjectsuch as a human, is initiated. In general, a detectable improvement isobserved in the subject within a period of about 3 days to about 12months after initiation of a dosing protocol, e.g., the severity of thedisease or condition will detectably decrease, the rate of progressionwill detectably slow or the severity of a symptom(s) will detectablydecrease.

As used herein, acute inflammation conditions are characterized as aninflammation that typically has a fairly rapid onset, quickly becomesmoderate or severe and usually lasts for only a few days or for a fewweeks. Chronic inflammation conditions as used herein are characterizedas an inflammation that may begin with a relatively rapid onset or in aslow, or even unnoticed manner, tends to persist for at least severalweeks, e.g., about 3-6 weeks, months, or years and may have a vague orindefinite termination. Chronic inflammation may result when theinjuring agent (or products resulting from its presence) persists in thelesion, and the subject's tissues respond in a manner (or to a degree)that is not sufficient to overcome completely the continuing effects ofthe injuring agent. Other exemplary conditions are described in, e.g.,Textbook of Autoimmune Diseases, R. G. Lahita, editor, LippincottWilliams & Wikins, Philadelphia, Pa., 2000, ISBN 0-7817-1505-9, pages175-851 and Rheumatology, 2^(nd) edition, J. H. Klippel et al., editors,1998, ISBN 0-7234-2405-5, volume 1, sections 1-5 and volume 2, sections6-8, Mosby International, London, UK.

A F1C can be used to inhibit or ameliorate one or more inappropriateimmune responses or their symptoms in autoimmunity, inflammation,allergy or related conditions. The effects of the F1Cs includedetectably ameliorating one or more of (1) the proliferation,differentiation or chemotaxis of T cells, (2) reducing unwantedcytotoxic T cell responses, (3) reducing unwanted autoantibody or otherantibody synthesis, e.g., an unwanted IgA, IgE, IgG or IgM, in allergy,asthma or another autoimmune or inflammation condition, (4) inhibitingthe development, proliferation or unwanted activity of autoreactive T orB cells, (5) altering the expression of one or more cytokines,interleukins or cell surface antigens, e.g., a cytokine, interleukin orcell surface antigen described herein (decreasing IL-8 in an autoimmunecondition, decreasing the level of acute phase proteins such as Creactive protein or fibrinogen in inflammation conditions, (6)decreasing eosinophilia in allergy conditions, (7) detectably decreasingthe level or activity of one or more of ICAM-1, IL-1α, IL-1β, TNFα, IL-6or IL-8 in, e.g., inflammation conditions or in autoimmune conditionssuch as an arthritis or a myocarditis condition such as osteoarthritis,rheumatoid arthritis, toxic myocarditis, indurative myocarditis oridiopathic myocarditis, (8) decreasing the level or biological activityof one or more of anti-islet antibody, TNF, IFN-γ, IL-1, an arthritissymptom(s), nephritis, skin rash, photosensitivity, headache frequencyor pain, migraine frequency or pain, abdominal pain, nausea or anti-DNAantibodies in, e.g., insulin dependent diabetes mellitus or anautoimmune or inflammation condition such as systemic lupuserythematosus, rheumatoid arthritis or Crohn's disease, (9) reducinginduction of arachidonic acid metabolism or reducing eicosanoidmetabolites such as thromboxanes or prostaglandins in, e.g.,inflammation, asthma or allergy, (10) reducing IL-4, IL-8 or IL-10synthesis, levels or activity in, e.g., allergy or inflammation such asidiopathic pulmonary fibrosis or allergic asthma or (11) reducing orinterfering with neutrophil chemotaxis by, e.g., reducing thioredoxinrelease from affected cells in conditions such as cancer, infections,inflammation or autoimmunity.

Exemplary symptoms that the use of the F1Cs can ameliorate in theseautoimmune, inflammatory and allergy conditions include one or more ofpain such as shoulder, hip, joint, abdominal or spine pain, jointstiffness or gelling, bursitis, tendonitis, edema or swelling, fatigueor malaise, headache, dyspnea, skin rash, fever, night sweats, anorexia,weight loss, skin or intestine ulceration, muscle weakness,pericarditis, coronary occlusion, neuropathy and diarrhea. In treatingone of these conditions in a subject or in improving one or moresymptoms thereof, the F1Cs may accomplish one or more of decreasinglevels of one or more of IL-1, IL-4, IL-6 or TNFα, decreasing levels ofC reactive protein, fibrinogen or creatinine kinase. Other biologicaleffects associated with treatment using a F1C may also be monitored orobserved, e.g., an increase or decrease of a cell surface antigen, acytokine or an interleukin as disclosed herein.

In another aspect of the invention, the F1Cs can be used to treat or toreduce the severity of chronic allergies or atopic diseases such asallergic rhinitis, psoriasis, eczema, gastrointestinal allergies, atopicdermatitis conditions, allergic asthma, food allergies and hay fever.These conditions are typically characterized by the presence of elevatedlevels of allergen specific antibodies of the IgE isotype. In treatingor ameliorating these conditions, the F1Cs reduce the generation of IgEby “isotype switching”, which is increasing allergen-specific IgAproduction and/or decreasing IgE production from preexistingallergen-primed cells. Allergen specific IgG may also be increased fromnew cells that might otherwise have responded to allergen exposure bygenerating unwanted IgE.

The IgA and IgG are allergen specific, which will enhance clearance ofallergen from mucosa or other tissue and reduction of chronic or latephase allergic responses. The F1C can thus also be used to increase thebiological clearance of allergens from tissue and mucosa. Reducedgeneration of the levels or activity of IgE by B cells in response totreatment with a F1C and related responses is facilitated at least inpart by decreased production of one or more biological responsemediators, e.g., cytokines or response mediators such as protein kinaseA inhibitors, substance P neuropeptide, thymus- and activation-regulatedchemokine, e.g., by airway smooth muscle cells, proteinase activatedreceptor-2 by neurons, intracellular signal-transducing protein-6(STAT6), Janus kinase 1, Janus kinase 6, CD40, CD86 and/or NF-kB by Bcells, CD154 in T cells, and suppressor of cytokine signalling-3,phosphodiesterase 4, TNF-α, MCP-1, RANTES, CXCL10, CXCL8 (IL-8),prostaglandin E2 receptor, IL-1β, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13,and IL-23, by one or more other cell types such as immune cells asdescribed herein, airway smooth muscle cells, mucosal cells orkeratinocytes. In these treatments, the F1Cs will also increase theactivity or levels of one or more desired response mediators includingsoluble CD23, cathepsin E, epidermal growth factor receptor, IFNγ, IL-2,IL-12 or IL-18. In treating these conditions, Treatment can be combinedwith other suitable therapies, e.g., corticosteroids such as fluticasonepropionate. The F1Cs can also be used to reduce rebound phenomenafollowing withdrawal of corticosteroid therapies, since the F1Cs have ananti-inflammatory effect without having immunosuppressive side effects.Use of the F1Cs to generate any of these biological responses ortreatments can be by daily or intermittent administration of the F1C tothe subject.

In a related embodiment, the F1Cs are used in allergen vaccinationprotocols to enhance levels or activity of allergen specific IgA or IgG,which contributes to reducing IgE responses to allergen exposure. Suchprotocols are used to decrease a subject's sensitivity to allergenexposure. Typically such allergies are chronic or atopic. In theseapplications, the vaccination protocol typically uses the allergen(s) oran active fragment(s) of the allergen that is associated with theallergy or atopic condition. In these methods, a F1C is administered toa subject who has an IgE mediated allergy or atopy condition inconjunction with administration of the allergen. Allergens typicallyused include dermatophagoides, house dust, cat allergen and pollen. Inany of these methods isotype switching or vaccination methods, the F1Cis typically administered as described herein, e.g., by administeringthe F1C about 1, 2, 3, 4, 5, 6, 7, 8, or more days before the allergenis administered to the subject. The subject may receive about 1-20 mg/kgof a F1C at 2, 3 and 4 days before the allergen is administered orinjected. The F1C treatment increases allergen specific IgA or IgGresponses or levels relative to untreated controls. The use of F1C withallergens will reduce the total number of anti-allergic vaccinationsthat are needed, increase the quality or length of an effective responseand/or increase the proportion of subjects in which allergy shots areeffective. An effective response is seen in about 55%, 60%, 65%, 70%,75%, 80% or more of vaccinated patients who also receive the F1Ccompared to about 40-50% of vaccinated patients who do not receive theF1C.

In treating inflammation or any condition described herein whereinflammation contributes to the condition, the F1Cs may detectablymodulate, e.g., decrease or increase, the expression or level oractivity of one or more biomolecules associated with the prevention,establishment, maintenance or progression of the inflammation condition.Such biomolecules include one or more of carcinoembryonic antigen,prostate specific antigen, her2/neu, Bcl-XL, bcl-2, p53, IL-1α, IL-1β,IL-6, or TNFα, GATA-3, COX-2, NFκB, IkB, an IkB kinase, e.g., IkBkinase-α, IkB kinase-β or IkB kinase-γ, NFAT, a ras protein such asH-ras or K-ras, cyclin D, cyclin E xanthine oxidase, or their isoforms,orthologs, homologs or mutant forms, which may have either reduced orenhanced biological activity(ies), and which may be detectablydecreased. Biomolecules that can be detectably increased include IL-2,IFNγ, IL-12, T-bet, O6-methylguanine-DNA-methyltransferase, calcineurin,calmodulin, a superoxide dismutase (e.g., Mn, Zn or Cu), a tumorsuppressor protein such as the retinoblastoma protein (Rb) or CDKN2A(p16), BRCA1, BRCA2, MeCP2, MBD2, PTEN, NBR1, NBR2 or the isoforms,orthologs, homologs or mutant forms, which may have either attenuated orenhanced biological activity(ies), of any of these molecules. One ormore of these biomolecules may be modulated in any inflammationcondition described herein.

The use of any F1C or species in any genus of F1Cs disclosed herein totreat, prevent or ameliorate any of these autoimmune, inflammatory orallergy conditions or symptoms will generally use one or more of theroutes of administration, dosages and dosing protocols as disclosedherein. Thus, in exemplary embodiments, about 0.5 to about 100 mg/kg orabout 1 mg/kg to about 15 mg/kg, of the F1C will be administered per dayby, e.g., an oral, buccal, sublingual, topical or parenteral route. Suchadministration can be, e.g., daily for about 5 to about 60 days in acuteconditions or it can be intermittent for about 3 months to about 2 yearsor more for chronic conditions. Alternatively, intermittent dosing canbe used essentially as described herein for acute autoimmune,inflammatory and allergy conditions.

In another aspect of the invention, the F1Cs can be used to treat or toreduce the severity of chronic allergies or atopic diseases such asallergic rhinitis, psoriasis, eczema, gastrointestinal allergies, atopicdermatitis conditions, allergic asthma, food allergies and hay fever.These conditions are typically characterized by the presence of elevatedlevels of the IgE isotype and of B cells that generate IgE. In treatingor ameliorating these conditions, the F1Cs reduce the generation of IgEby facilitating an isotype switch from B cells that produce IgE to cellsthat produce antigen-specific IgA and/or IgG4. The IgA and IgG4 areallergen specific, which will facilitate clearance of allergen frommucosa or other tissue and reduction of chronic or late phase allergicresponses. The F1c can thus be used to increase the biological clearanceof allergens from tissue. Reduced generation of the levels or activityof IgE by B cells in response to treatment with a F1C and relatedresponses is facilitated at least in part by decreased production of oneor more biological response mediators, e.g., cytokines or responsemediators such as protein kinase A inhibitors, substance P neuropeptide,thymus- and activation-regulated chemokine, e.g., by airway smoothmuscle cells, proteinase activated receptor-2 by neurons, intracellularsignal-transducing protein-6 (STAT6), Janus kinase 1, Janus kinase 6,CD40, CD86 and/or NF-κB by B cells, CD154 in T cells, and suppressor ofcytokine signalling-3, phosphodiesterase 4, TNF-α, MCP-1, RANTES,CXCL10, CXCL8 (IL-8), prostaglandin E₂ receptor, IL-1β, IL-4, IL-5,IL-6, IL-10, IL-13 and IL-18 by one or more other cell types such asimmune cells as described herein, airway smooth muscle cells, mucosalcells or keratinocytes. In these treatments, the F1Cs will also increasethe activity or levels of one or more desired response mediatorsincluding cathepsin E, epidermal growth factor receptor, IFNγ, IL-2,IL-12. In treating these conditions, Treatment can be combined withother suitable therapies, e.g., corticosteroids such as fluticasonepropionate. The F1Cs can also be used to reduce rebound phenomenafollowing withdrawal of corticosteroid therapies, since the F1Cs have ananti-inflammatory effect without having immunosuppressive side-effects.Use of the F1Cs to effect any of these biological responses ortreatments can be by daily or intermittent administration of the F1C tothe subject.

In a related embodiment, the F1Cs are used to enhance isotype switchingfrom IgE to IgG in these chronic allergies or atopic diseases invaccination protocols that use the allergen(s) or an active fragment(s)of the allergen that is associated with the allergy or atopic condition.In these methods, a F1C is administered to a subject who has an elevatedIgE allergy or atopy condition in conjunction with administration of theallergen. The subject's response to the allergen is an enhancedproportion of B cells that produce IgG compared to B cells that generateIgE. Allergens typically used include dermatophagoides, house dust, catallergen and pollen. In these methods, the F1C is typically administeredabout 1, 2, 3, 4, 5, 6, 7, 8, or more days before the allergen isadministered to the subject, e.g., the subject receives about 1-20 mg/kgof a F1C at 2, 3 and 4 days before the allergen is administered orinjected. The F1C facilitates isotype switching to IgG. The use of F1Cwith allergens will reduce the total number of anti-allergicvaccinations that are needed, increase the quality or length of aneffective response and/or increase the proportion of subjects in whichallergy shots are effective, e.g., an effective response is seen inabout 55%, 60%, 65%, 70%, 75%, 80% or more of vaccinated patients whoalso receive the F1C compared to about 40-50% of vaccinated patients whodo not receive the F1C.

The F1Cs are suitable for enhancing immune responses in aging insubjects such as humans or primates. In humans at about 50 to 60 yearsof age and later, one or more aspects of immune responses will typicallydecrease by a detectable amount compared to typical immune responses atyounger ages, e.g., at about 18-50 years of age. The F1Cs can be used onan intermittent basis or continuously in aged subjects. Intermittentadministration of a F1C can occur as described herein, e.g., dailydosing or dosing every other day or every third day for about 1, 2, 3,4, 5, 6, 7, 8 or 9 days, followed by about 2, 3, 4, 5, 6, 7, 8, 9 or 10weeks of no dosing, optionally followed by about 1, 2, 3, 4, 5, 6, 7 or8 days of daily dosing or dosing every other day or every third day andthen followed by about 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks of no dosing.Such dosing cycles can be repeated indefinitely or as needed. Suchtreatments can be used prophylactically or therapeutically. Inprophylaxis the F1C are administered, e.g., before or during influenzaoutbreaks, or in aged patients in hospitals or in aged patients in longterm living or care facilities such as retirement communities or nursinghomes. In therapeutic applications, the F1C are used to treat trauma,e.g., bone fractures or active infections. The F1C treatments in theseembodiments will result in enhanced immune responses, includingincreased innate and specific responses to, e.g., infectious agents.These treatments will typically also have other beneficial effectsincluding enhancing bone marrow production of blood cells or bloodcomponents such as neutrophils or improving levels of dysregulatedimmune response mediators, e.g., decreasing elevated cortisol, IL-6,IL-10, COX-2 or C reactive protein levels or increasing low IL-2 orIL-12 levels.

In related embodiments, the use of the F1C is optionally combined withone or more additional known or experimental therapies for anautoimmune, inflammatory or allergy disorder(s), e.g., one or more ofsurgery and treatment with a corticosteroid or glucocorticoid such ashydrocortisone, hydrocortisone acetate, fludrocortisone, prednisone,prednisolone, prednisolone acetate, methylprednisolone, dexamethasone,dexamethasone acetate or triamcinolone acetonide, leflunomide, anantibody, e.g., a human or humanized monoclonal antibody, that decreasesthe activity or level of C5 complement, TNFα or TNFα receptor, anantirheumatic drug such as methorexate, D-penicillamine, sodiumaurothiomalate, sulfasalazine or hydroxychloroquine, immunosuppressiveagents such as 6-thioguanylic acid, chlorambucil, cyclophosphamide orcyclosporin, a non-steroidal antiinflammatory agent such as celecoxib,ibuprofin, piroxicam or naproxin, an antihistamine such as loratidine orpromethazine hydrochloride, an analgesic such as propoxyphene napsylate,acetaminophen or codeine or administration of vitamins (e.g.,multivitamins, individual vitamins), antioxidants or other agents (e.g.,vitamin E, folinic acid, carnitine, a C2-8 alkanoyl carnitine such asacetyl or propionyl L-carnitine) or nutritional supplements (e.g.,liquid protein or carbohydrate preparations). Such therapies would beused essentially according to standard protocols and such they wouldprecede, be concurrent with or follow treatment with a F1C. In someembodiments, such additional therapies will be administered at the sametime that a F1C is being used or within about 1 day to about 16 weeksbefore or after at least one round of treatment with the F1C iscompleted. Other exemplary therapeutic agents and their use have beendescribed in detail, see, e.g., Physicians Desk Reference 54^(th)edition, 2000, pages 303-3267, ISBN 1-56363-330-2, Medical EconomicsCo., Inc., Montvale, N.J. One or more of these exemplary agents can beused in combination with a F1C to ameliorate, prevent or treat any ofthe appropriate autoimmune, inflammatory or allergy conditions ordisorders described herein or any of their symptoms.

Where a natural or synthetic antiinflammatory glucocorticoid is used totreat one more of the conditions disclosed herein or wherein endogenouslevels of glucocorticoid such as cortisol are elevated to an unwantedlevel in a subject, the use of a F1C will ameliorate unwantedside-effects of such glucocorticoid use or excess. Typically the F1Cwill be administered during, before and/or after glucocorticoid levelsare elevated or during, before and/or after a therapeutic glucocorticoidis administered to the subject, e.g., within about 1, 2, 3, 4, 5, 6 or 7days or within about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 20 or24 weeks before or after glucocorticoid use or elevated glucocorticoidlevels exist. Typically, the use of the F1C to counteract unwantedside-effects of therapeutic glucocorticoid use In these embodiments,will reduce or ameliorate the onset, severity or progression of one ormore unwanted side-effects of glucocorticoid therapy such as adetectable immune suppression, an increased occurrence or incidence ofinfection, an undesirable alteration of mood (e.g., increased anxiety,depression or schizophrenia) or a detectable loss or alteration ofmemory.

Regeneration and wound healing. The F1Cs can be used to facilitate celldifferentiation, proliferation or repair where regeneration of tissuesis desired. The regeneration of tissues could be used to repair,replace, protect or limit the effects of tissue damaged by congenitaldefects, trauma (wounds, burns, incisions, or ulcers), age, disease(e.g. osteoporosis, osteoarthritis, periodontal disease, liver failure),surgery, including cosmetic plastic surgery, fibrosis, reperfusioninjury, toxin exposure or systemic cytokine damage. Ulcers or skinlesions can arise from ionizing radiation exposure, cytotoxicchemotherapy or pressure, e.g., a pressure or decubitis ulcer orvascular insufficiency, e.g., associated with diabetes or vascularocclusion. Tissues for which regeneration may be enhanced include organs(e.g., pancreas, liver, lung, intestine, kidney, skin, endothelium, oralmucosa, gut or intestinal mucosa), muscle (e.g., smooth, skeletal orcardiac), vasculature (including vascular and lymphatics), central orperipheral nervous tissue, hematopoietic tissue, and skeletal tissue(e.g., bone, cartilage, tendon, and ligament). Decreased scarring or anincreased rate or quality of healing may accompany these effects.

The F1Cs are thus useful to enhance healing or tissue repair in asubject having a bone fracture(s), e.g., a simple or compound skull,spine, hip, arm or leg bone fracture. Similarly, nerve or brain tissuetreatment using a F1C allows treating, slowing the progression of,ameliorating or preventing diseases such as central and peripheralnervous system diseases, neuropathies, or mechanical and traumaticdiseases, disorders, and/or conditions (e.g., spinal cord disorders,head trauma, cerebrovascular disease, and stoke). The compounds areuseful to treat diseases associated with peripheral nerve injuries,peripheral neuropathy (e.g., resulting from chemotherapy, radiationexposure or therapy or other medical therapies), localized neuropathies,and central nervous system diseases such as Alzheimer's disease,Parkinson's disease, Huntington's disease and amyotrophic lateralsclerosis. The subjects undergoing treatment in these conditions may beelderly, e.g., a human at least about 55, 60, 65 or 70 years of age.Where the condition is acute, e.g., a bone fracture or a burn, thetreatment may comprise administration of a F1C to the subject on a dailyor intermittent basis for about 3 days to about 12 months, e.g.,administration for about 2-12 weeks beginning after the subject sustainsan injury.

An aspect of the F1Cs is their capacity to facilitate wound or traumahealing by increasing the proliferation or self-renewal of stem cellsand pluripotent derivatives of stem cells and/or the rate ofdifferentiation of stem cells or their pluripotent derivatives to maturecell types. Thus, the F1Cs can increase the numbers, rate ofdifferentiation or activity of stem cells in, e.g., skin, central ornervous system tissue, blood vessels, heart tissue, lung, liver,pancreas, kidney, thymus, spleen, oral mucosa, intestine or bone marrow,some of which is discussed elsewhere herein. Increased numbers of maturecell types typically is observed beginning at about 2-28 days aftertreatment with a F1C is started, usually after about 2-21 days. Thus,the F1Cs can enhance the numbers, activities or differentiation of,e.g., crypt cells in intestinal mucosa, skin stem cells in the oralmucosa or cardiac precursor cells after damage to those cells ortissues. Such damage can arise, e.g., from trauma, infection, ionizingradiation exposure, toxin exposure and/or cytotoxic chemotherapy.Optimal modulation of stem cell survival, self-renewal anddifferentiation in these embodiments is usually obtained by dosing theF1C at a time period near the time that the subject is exposed to anagent, event or treatment that can cause significant tissue damage.Typically this time period is about 1, 2, 3, 4 or 5 days before, on thesame day as or within 1, 2, 3, 4 or 5 days after the damaging event orexposure occurs. For chronic toxin exposure, e.g., alcohol, chroniccontinuous or intermittent administration of the F1C can be used.Dosages of the F1Cs, routes of administration and dosing protocols forthese embodiments are as described herein.

As noted above, the F1Cs are useful to enhance healing in a subject whohas experienced or who is expected to experience one or more traumas oracute injuries such as a wound, burn, bone fracture, nervous systemtissue trauma, gastrointestinal damage or intestinal cell damage orother traumatic events. In some embodiments, such subjects haveexperienced a trauma and who are immune suppressed or are anticipated tobecome immune suppressed. The immune suppression may arise from, e.g., amyelosuppressive cancer therapy, a glucocorticoid therapy or fromradiation exposure. Thus, in some cases a subject such as a human or aprimate who has experienced a trauma, e.g., a bone fracture, a chemicalor thermal burn, a cut or a laceration, is also exposed to, e.g., anionizing radiation as described herein such as γ-radiation, β-radiation,X-radiation or neutron radiation in an immune suppressive amount ordose, e.g., about 0.3 Gy (“gray”) to about 30 Gy, typically about 0.5 Gyto about 12 Gy or about 0.7 Gy to about 8 Gy. The subject's radiationexposure can be localized or whole body and can occur rapidly, e.g.,over a period of up to about 20 minutes, or more slowly, e.g., over aperiod of about 5-25 minutes to about 5-72 hours or more. A Gy ofradiation is 1 joule per kg of absorbed ionizing radiation. The traumaevent and the radiation exposure event may occur at about the same time,e.g., on the same day, or within a time period of about 1, 2, 3, 4, 5 or6 days to about 1, 2, 3 or 4 weeks, when detectable clinical effects ofboth events are present. Treatment with the F1C will use the dosingprotocols, dosages and routes of F1C administration as described herein,e.g., dosing daily or every other day for about 1-12 days using dosagesof about 0.1 mg/kg to about 30 mg/kg, depending on the route ofadministration and the subject's condition. Dosing of the F1C willusually commence within a few days of the radiation exposure event,e.g., within 0, 1, 2, 3 or 4 days. Similarly, such healing or repair oftraumas in subjects who are or are expected to become immune suppressed,e.g., from an immunosuppressive chemotherapy, cancer, stress, infectionor from aging, can be treated in the same manner.

Neurological conditions. Nervous system diseases, disorders, conditions,or their symptoms (collectively ‘neurological conditions’) that can beameliorated, treated or prevented with any of the F1Cs disclosed hereininclude, but are not limited to, nervous system trauma or injury, andneurological conditions that result in an unwanted pathology or symptom,e.g., demyelination, pain, impairment of cognitive function, discernablememory loss, depression, anxiety, a disconnection of axons, a diminutionof neuron, astrocyte or glia function or degeneration or death ofnervous system cells or tissues such as one or more of those describedherein.

Neurological conditions, including nervous system lesions that may betreated, prevented, or ameliorated in a subject include but are notlimited to, the following lesions of either the central (includingspinal cord, brain) or peripheral nervous systems. Exemplaryneurological conditions include (1) ischemic lesions, in which a lack ofoxygen in a portion of the nervous system results in neuronal injury ordeath, including cerebral infarction, ischemia or stroke, or spinal cordinfarction or ischemia, (2) traumatic lesions, including lesions causedby physical injury or associated with surgery, for example, lesionswhich sever a portion of the nervous system, or compression injuries,(3) malignant lesions, in which a portion of the nervous system isdestroyed or injured by malignant tissue which is either a nervoussystem associated malignancy or a malignancy derived from non-nervoussystem tissue, (4) infectious lesions, in which a portion of the nervoussystem is destroyed or injured as a result of infection, for example, byan abscess or associated with infection by human immunodeficiency virus,herpes zoster, or herpes simplex virus or with Lyme disease,tuberculosis or syphilis, (5) degenerative lesions or conditions, inwhich a portion of the nervous system is destroyed or injured as aresult of a degenerative process including but not limited todegeneration associated with Parkinson's disease, Alzheimer's disease,Huntington's chorea, AIDS associated dementia, eplieptic dementia,presenile dementia, senile dementia, vascular dementia, post strokedementia, post traumatic dementia or amyotrophic lateral sclerosis(ALS), (6) lesions associated with nutritional diseases, disorders,and/or conditions, in which a portion of the nervous system is destroyedor injured by a nutritional disorder or disorder of metabolism includingbut not limited to, vitamin B 12 deficiency, folic acid deficiency,Wernicke disease, tobacco-alcohol amblyopia, Marchiafava-Bignami disease(primary degeneration of the corpus callosum), and alcoholic cerebellardegeneration, (7) neurological lesions associated with systemic diseasesincluding, but not limited to, diabetes (diabetic neuropathy, Bell'spalsy), systemic lupus erythematosus, carcinoma, or sarcoidosis, (8)lesions caused by toxic substances including alcohol, lead, orneurotoxins, (9) demyelinated lesions in which a portion of the nervoussystem is destroyed or injured by a demyelinating disease including, butnot limited to, multiple sclerosis, human immunodeficiencyvirus-associated myelopathy, progressive multifocal leukoencephalopathy,and central pontine myelinolysis or a myelopathy, e.g., diabeticmeylopathy or a transverse myelopathy, (10) neurological conditions suchas insomnia (e.g., transient or chronic), epilepsy, schizophrenia,psychosis, delusion, a unipolar mood disorder, a bipolar mood disorder,psychomotor dysfunction, depression, anxiety, addiction to or abuse of adrug substance such as tobacco, nicotine, caffeine, alcohol, abarbiturate, a tranquilizer, a narcotic such as hydromorphone HCl,propoxyphene napsylate, meperidine HCl, valium, codeine, cocaine,morphine, heroin or methadone, (11) cognitive dysfunction conditions ordiseases such as one or more of impaired long-term or short-term memory,impaired concentration, impaired attention or impaired learning, wherethe cognitive dysfunction condition or disease is optionally associatedwith chemotherapy, radiation therapy or exposure, aging, trauma, e.g.,CNS trauma, or neurodegeneration and (12) genetic disorders with aneurological pathology or component such as Down's syndrome or TaySach's disease.

The F1Cs are useful to ameliorate, treat or prevent the onset, severityor length of other neurological diseases or conditions such as headacheor a migraine condition or symptom such as classic migraine, clusterheadache, abdominal migraine, common migraine, hemiplegic migraine,ocular migraine, fulminating migraine, complicated migraine or a symptomof any of these such as head pain, vertigo, nausea, vomiting orpotophobia.

In some embodiments, the F1C is used to protect neural cells from thedamaging effects of cerebral hypoxia, cerebral ischemia or neural cellinjury associated with cerebral infarction, heart attack, stroke orelevated levels of glucocorticoids such as cortisol. The compounds thatare also useful for treating or preventing a nervous system disorder maybe selected, e.g., by assaying their biological activity in promotingthe survival or differentiation of neurons. For example, and not by wayof limitation, the F1Cs can be used to elicit any of the followinguseful effects: (1) increased survival time of neurons in culture, (2)increased sprouting of neurons in culture or in vivo, (3) increasedproduction of a neuron-associated molecule in culture or in vivo, e.g.,dopamine or choline acetyltransferase or acetylcholinesterase withrespect to motor neurons or (4) decreased symptoms of neuron dysfunctionin vivo. Such effects may be measured by any method known in the art.Increased survival of neurons may be measured using known methods, suchas, for example, the method set forth in Arakawa et al. (J. Neurosci.10:3507-3515 1990); increased sprouting of neurons may be detected bymethods known in the art, such as the methods set forth in Pestronk etal. (Exp. Neurol. 70:65-82 1980) or Brown et al. (Ann. Rev. Neurosci.4:17-42 1981). Increased production of neuron-associated molecules maybe measured by, e.g., bioassay, enzymatic assay, antibody binding orNorthern blot assay, using techniques known in the art and depending onthe molecule to be measured. Motor neuron dysfunction may be measured byassessing the physical manifestation of motor neuron disorder, e.g.,weakness, motor neuron conduction velocity, or functional disability.Motor neuron conditions may arise from infarction, cancer, infection,exposure to toxin, trauma, surgical damage or a degenerative diseasethat affects motor neurons as well as other components of the nervoussystem.

Other neurological conditions that can be treated using F1Cs includeconditions that selectively affect neurons or adjacent tissues such asamyotrophic lateral sclerosis, progressive spinal muscular atrophy,progressive bulbar palsy, primary lateral sclerosis, infantile andjuvenile muscular atrophy, poliomyelitis and the post polio syndrome,hereditary motorsensory neuropathy, spinal cord compression and amyelitis such as necrotizing myelitis, transverse myelitis, ascendingmyelitis, bulbar myelitis, concussion myelitis, demyelinated myelitis,postinfectious myelitis, systemic myelitis or transverse myelitis.

In some neurological conditions such as mood changes, depression,anxiety, memory loss or motor function impairment, the F1Cs can modulateone or more biological activities of a transcription factor or a nuclearhormone receptor such as ERα in tissue such as the hypothalamus oramygdala or ERβ in tissue such as the hippocampus, thalamus orentorhinal cortex.

In neurological conditions or other conditions where loss or damage tonervous system cells or tissue is typically present, e.g., multiplesclerosis, cerebral infarction, cerebral trauma, elevated glucocorticoidlevels or Alzheimer's disease, use of the F1Cs can lead to detectablerepair of damaged cells or replacement of at least some killed cells.Elevated glucocorticoids can result from endogenous production ofnatural glucocorticoids, e.g., cortisol or hydrocortisone, or fromadministration of synthetic glucocorticoids, e.g., dexamethasone,triamcinolone, betamethasone or other synthetic agents disclosed hereinor in the cited references. Repair or replacement can occur for celltypes that are present in nervous system tissues, e.g., neurons, Schwanncells, glial cells, astrocytes, oligodendrocytes, macroglia cells,endothelial cells, or stem or progenitor cells of any of these celltypes. The cells may reside in discrete regions of nervous organs, e.g.,hippocampus, cerebrum or cerebellum, or they may reside in multipleregions. Any of the neurological conditions that can be treated with theF1Cs may be acute, subacute or chronic and they may be subclinical(having few or no overt symptoms), mild, moderate or severe.

In treating neurological conditions, the F1Cs will generally enhancefunction, self renewal and/or differentiation of stem or progenitorcells and/or they will reduce the severity of cell damage or impairmentcompared to similar subjects that are not treated with the F1Cs. Incases where myelin damage or nerve death occurs, the F1Cs can reduce therate at which damage or death occurs or they can detectably reversedamage or enhance replacement of killed cells, particularly where theextent of such damage or killing is mild or moderate. Without wishing tobe bound to any theory, the F1Cs may exert these properties (1) bydirectly acting as a hormone, growth factor or modulator of abiomolecule disclosed herein such as an enzyme, a glucocorticoidreceptor, PPARα, a neural stem cell helix-loop-helix transcriptionfactor such as HES1 or an estrogen receptor to enhance replication,synaptogenesis or other repair or maintenance functions, (2) byenhancing recruitment and/or differentiation of cells involved in cellor tissue repair, e.g., enhanced recruitment and differentiation ofoligodendrocyte cells to a demyelinated lesion in multiple sclerosisand/or (3) indirectly by modulating the level or activity of autocrine,paracrine or endocrine factors such as one or more inflammatorycytokines or markers as disclosed herein that can modulate diseaseprogression, e.g., cortisol, IL-1α, IL-1β, TNF-α, IL-6, a thromboxane, aprostaglandin or a neuregulin.

In treating chronic or progressive disorders such as multiple sclerosisor Alzheimer's disease, the F1Cs will typically slow the rate ofprogression of the disease. The F1Cs act at least in part by decreasingthe activity or levels of chemokines and/or pro-inflammatory cytokines,e.g., one, two or more of MCP-1, MIP-1, ICAM, V-CAM, E-selectin, RANTES,IL-1α, IL-1β, IL-6, IL-8 and TNF-α. This reduction can be accompanied bya reduced rate of deposition of amyloid-β (AJ3) protein, which resultsin slowed disease progression and in reduced severity and/or frequencyof one or more symptoms such as short term memory loss, impairedconcentration, impaired judgement, episodes of disorientation orconfusion and periods of mood or behavior changes such as irritability,anxiety or aggression. Treatment of chronic or progressive disorderssuch as Alzheimer's disease with a F1C is optionally accompanied byother suitable treatments, e.g., treatment with one or morenon-steroidal anti-inflammatory drugs or other palliative measures.

Factors such as increased levels of cortisol or thromboxane, that areassociated with increased cell or tissue damage or with inhibition ofcell growth or differentiation are generally decreased or reregulated toexpress in a normal manner by the appropriate cells such as neurons,astrocytes, glial cells or their stem or precursor cells. Factors thatfacilitate normal differentiation or repair, e.g., basic fibroblastgrowth factor 2 or neuregulin, are generally increased or reregulated toexpress in a normal manner by the appropriate cells such as neurons,astrocytes, glial cells or their stem or precursor cells.

Because of these properties, the F1Cs can be used in various protocolsor methods to enhance differentiation or proliferation of these celltypes in vivo or in vitro. Typically, the concentration of the F1Cs willexert one or more of these beneficial effects at extracellularconcentrations of about 1×10⁻¹² M to about 5×10⁻⁶ M, e.g., about 1×10⁻¹¹M to about 5×10⁻⁷ M or about 1×10⁻¹⁰ M to about 1×10⁻⁷ M. Suchconcentrations can suitably be established transiently, e.g., for about10 minutes to about 6 hours or about 12 hours once or twice per day onone, two or more days. Alternatively, such concentrations may bemaintained more or less constantly, e.g., within these ranges for atleast about 12 hours per day for one, two or more days, particularly forin vitro use to enhance cell or tissue growth, differentiation orviability in tissue culture. Methods to administer the F1Cs for in vivouse are essentially as described herein.

For any of these neurological conditions or their associated symptoms,the presence of the condition or its pathological manifestation, e.g.,cell or tissue damage, or symptom may be determined by suitableobjective or subjective means, e.g., assays to detect tissue damage,levels of diagnostic markers or an etiological agent, performance ofhistopathological examination of cells or tissues, patientquestionnaires or behavior performance tests, measurement of adiagnostic marker(s), e.g., an enzyme, hormone, cytokine or drugsubstance in blood or tissue, electroencephalography, imaging methodssuch as X-ray, MRI scan or CAT scan, observation and diagnosis ofclinical features or symptoms or biopsy of affected tissue or cells,e.g., aspiration biopsy, needle biopsy, incision biopsy or punch biopsyof tissue or cells. Neurological conditions, diseases and symptoms,which the F1Cs can be used to treat or ameliorate and methods todiagnose and characterize such conditions or diseases have beendescribed. See, e.g., Ph. Demaerel, A. L. Baert et al., eds. RecentAdvances in Diagnostic Neuroradiology (Medical Radiology: DiagnosticImaging) 2001 Springer Verlag, ISBN: 3504657231, W. G. Bradley et al.,Neurology in Clinical Practice: Principles of Diagnosis and Management1995, see, e.g., vol. 1 Ch. 1-55 and vol. 2. Ch. 1-66,Butterworth-Heinemann Medical, ISBN 0750694777, H. J. M. Barnett et al.,eds. Stroke: Pathophysiology, Diagnosis and Management 3^(rd) edition,1998, see, e.g., pages 10-1450, Churchill Livingstone, ISBN 0443075514,P. J. Vinken et al., eds. Neurodystrophies and Neurolipidoses 2^(nd) ed.1996, see, e.g., pages 8-780, Elsevier Science, ISBN 0444812857, P. L.Peterson and J. W. Phillis eds. Novel Therapies for CNS Injuries:Rationales and Results 1995, see, e.g., pages 8-380, CRC Press, ISBN0849376521, D. Schiffer, Brain Tumors: Pathology and Its BiologicalCorrelates 2^(nd) ed. 1997, see, e.g., pages 5-450, Springer Verlag,ISBN 3540616225 and E. Niedermeyer and F. Lopes Da Silva, eds.Electroencephalography: Basic Principles, Clinical Applications andRelated Fields 4^(th) ed. 1999 see, e.g., pages 13-1238, Lippincott,Williams & Wilkins, ISBN 0683302841.

The use of the F1Cs in these conditions is optionally combined with oneor more of the therapeutic treatments that are described in thesereferences. The F1C may be administered before, during or after anothertreatment is employed to prevent, treat or ameliorate a givenneurological condition or symptom thereof. Any of these neurologicalconditions or symptoms may be mild or at an early stage, moderate orsevere or advanced.

Dosages of the F1C, routes of administration and the use of combinationtherapies with other standard therapeutic agents or treatments could beapplied essentially as described above for cardiovascular conditions oras disclosed elsewhere herein. Thus, the F1Cs may be administeredprophylactically or therapeutically in chronic conditions or they may beadministered at the time of or relatively soon before or after an acuteevent such as an epileptic seizure, onset of a migraine or occurrence oftrauma, before, during or after surgery, accidental head or centralnervous system injury or a cerebral stroke or infarction. For acuteevents, the formula 1 compounds may thus be administered concurrently,e.g., within about 15 minutes or about 30 minutes of the onset oroccurrence of the acute event, or at a later time, e.g., at about 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24, 26, 28,30, 36, 42, 48, 54, 60, 72, 84, 96, 108 or 120 hours after the onset oroccurrence of the acute event. The F1Cs may thus be administered atabout 6-120 hours, or about 8-48 hours, about 10-24 hours or about 12-16hours after an acute event starts or occurs. In other embodiments, theF1C can be administered before an expected acute event such as a plannedsurgery. In these cases, the F1Cs may be administered before, e.g.,within about 15 minutes or about 30 minutes of the onset or occurrenceof the acute event, or at an earlier time, e.g., at about 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24, 26, 28, 30, 36,42, 48, 54, 60, 72, 84, 96, 108 or 120 hours before the onset oroccurrence of the acute event.

Skin treatments. The affect of the F1Cs on immune function permits theiruse to improve the function of organs or organ systems that rely on theoptimal functioning of one or more immune responses. Thus, the F1Cs canbe administered to a subject to prevent, treat, ameliorate, slow theprogression of or enhance the healing of certain skin conditions such asskin inflammation, lesions, atrophy or rash. Conditions that can giverise to skin pathology or an unwanted skin condition include autoimmunediseases, inflammation, allergy, age, exposure to sunlight, cancer,infection or the like.

As used here, skin includes external skin and internal skin or surfacessuch as oral, intestinal and rectal mucosa. These conditions includelesions, rashes or inflammation associated with, e.g., burns, infectionsand the thinning or general degradation of the dermis oftencharacterized by a decrease in collagen or elastin as well as decreasednumber, size and doubling potential of fibroblast cells. Such skinconditions include keratoses such as actinic keratosis, psoriasis,eczema, warts such as papillomavirus-induced warts, ulcers or lesionssuch as herpesvirus-induced ulcers or lesions or diabetes associatedulcers or lesions, discoid lupus erythematosus, erythema nodosum,erythema multiform, cutaneous T cell lymphoma, atopic dermatitis,inflammatory vasculitis, relapsing polychondritis, exfoliativedermatitis, sarcoidosis, burns, melanoma, rash or irritation from poisonoak, poison ivy or poison Sumac, blemished or hyperpigmented skin,hyperkeratotic skin, dry skin, dandruff, acne, inflammatory dermatoses,scarring such as from a chemical or thermal burn and age-related skinchanges. In these embodiments, treatment with the F1Cs is optionallycombined with other appropriate treatments or therapies essentially asdescribed herein, e.g., one or more of a corticosteroid such ashydrocortisone or cortisol, prednisone, or prednisolone, anα-hydroxybenzoic acid or an α-hydroxycarboxylic acid(s) iscoadministered with a F1C to treat, prevent or ameliorate a skincondition such as atrophy or a lesion. α-Hydroxybenzoic acids andα-hydroxycarboxylic acids suitable for use in these embodiments aredescribed in, e.g., U.S. Pat. Nos. 5,262,407, 5,254,343, 4,246,261,4,234,599 and 3,984,566. The F1C can be used to minimize cutaneousatrophy caused by corticosteroids, a side effect of their application tothe skin.

In these embodiments that address skin conditions, dosages, routes ofadministration and dosing protocols for the F1Cs are essentially asdescribed herein. In some embodiments, the F1C is administered to thesubject in the form of a topical cream, ointment, spray, foam or gel.These topical formulations will optionally comprise about 0.1% w/w toabout 20% w/w, or about 0.2% w/w to about 10% w/w of a F1C in acomposition that comprises one or more excipients that are suitable forsuch topical formulations, including, e.g., one or more agents thatenhance penetration or delivery of the F1C into the skin. Such topicalformulations can be administered, e.g., once, twice or three times perday using about 0.1 g to about 8 g or about 0.2 g to about 5 g of thetopical formulation on each occasion. Administration may be daily forabout 1 to about 28 days, or it may be intermittent and used as needed.The amount of a topical formulation that can be administered may behigher, e.g., about 15 g or about 20 g, if the size of the area to betreated is relatively large, e.g., at least about 30 cm² to about 100cm² or more. Alternatively, systemic administration of the F1C such asoral, parenteral, sublingual or buccal delivery may be used,particularly when the area of the skin to be treated is relativelylarge. In some cases, both topical and systemic administration of a F1Ccan be used. Excipients that topical or other formulations may containinclude those described herein, or agents that enhance permeation orsolubilization of the F1C, e.g., DMSO or an alkylalkanol, such as a2-alkylalkanol or a 3-alkyloctanol that comprises about 8-36 carbonatoms (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbonatoms) such as 2-ethyloctanol, 2-propyloctanol, 2-octyldodecanol,2-butyloctanol, 2-hexyldecanol, 2-pentylnonanol, 3-ethyloctanol,3-propyloctanol, 3-octyldodecanol, 3-butyloctanol, 3-hexyldecanol,3-pentylnonanol, isostearyl alcohol, isocetyl alcohol, or mixturesthereof. Such alkylalkanol moieties include those having the structureHO—CH₂—(CH₂)₀₋₄—CH(C1-10 alkyl)-(CH₂)₀₋₆—CH₃, any of which areoptionally substituted at the alkanol or the alkyl moiety with one, two,three or more independently selected substituents as described herein,e.g., with one, two, three or more independently selected —O—, —F, —OH,—CN or —CH═CH— moieties. Such formulations can be used in therapeuticapplications described herein or in cosmetic applications.

Enhancement of hematopoiesis. The invention includes methods to modulatehematopoiesis by administering a F1C to a subject, which can be used totreat or prevent various blood cell deficiencies such asthrombocytopenia (“TP”) or neutropenia (“NP”). Hematopoiesis orhemopoiesis is the formation and development of the various types ofblood cells and their progenitor cells. Mature cells are found incirculation or tissues such as the lymph nodes, spleen or the thymus.Many of the stem cells that give rise to mature forms reside in the bonemarrow, although some may circulate in the blood for some time. Clinicalblood cell deficiencies such as thrombocytopenia, neutropenia orerythropenia can arise from causes such as impaired hematopoiesis orabnormal loss or destruction of mature or immature blood cells.

Without being bound to any theory, the treatment methods at least inpart result in enhanced hematopoiesis, enhanced movement of blood cellsinto the circulation and/or in reduced loss of blood cells such asplatelets or neutrophils. The F1Cs can enhance self-renewal or numbersof hematopoietic stem cells, precursor cells, mature blood cells and/orthey can enhance or accelerate differentiation of stem or any progenitorcell that can give rise to a mature blood cell. The stem or progenitorcells include early lineage cells showing little or no characteristicsof fully differentiated blood cells and/or they can be partiallydifferentiated. Increased platelet or neutrophil production, enhancedsurvival or reduced loss is typically observed as increased circulatingblood cell counts. Increases in blood cells appear to arise fromenhanced proliferation of precursor cells and/or from enhanced oraccelerated differentiation of precursor cells. Increased cell numbers,e.g., platelets or neutrophils, can also arise from reduced loss ordeath of such cells, increased demargination of cells such asneutrophils from the vasculature into circulating blood or other tissuesand/or shorter transit time of mature or precursor cells from the bonemarrow into blood.

Thus, invention embodiments comprise a method to treat or prevent ablood cell deficiency such as TP or NP in a subject in need thereof,comprising administering to the subject, or delivering to the subject'stissues, an effective amount of a F1C. Related embodiments include amethod to increase self-renewal of hematopoietic stem cells orhematopoietic progenitor cells or to increase the commitment of suchcells to transition to a more differentiated blood precursor cell ormature blood cell. In other embodiments, the invention provides a methodfor stimulating the proliferation or differentiation of neutrophilprecursors or to increase demargination of neutrophils or to reducetransit time from bone marrow to blood in a subject having orsusceptible to developing NP comprising administering an effectiveamount of a F1C to the subject in need thereof. The F1C treatment willstimulate the activity of, e.g., neutrophils, or enhance theirproduction from progenitor cells, enhance their survival and/or limittheir loss. Hematopoietic stem cells, e.g., GEMM cells, are pluripotentand can give rise to more than one type of mature blood cell, whilehematopoietic progenitor cells are usually not pluripotent, but arebipotent or monopotent. Hematopoietic progenitor cells reside primarilyin bone marrow, but can also be found in blood, spleen or lymph tissueor fluids.

Normal ranges of various white blood cells or blood components in adult(about 18-49 years of age) human blood are as follows. Total adult whiteblood cell counts average about 7500/mm³, with an approximate normalrange of about 4.5−11.0×10³/mm³. The normal basophil level is about35/mm³, with a normal range of about 10/mm³ to about 100/mm³. The normaladult neutrophil level is about 4400/mm³, with a normal range of about2000-7700/mm³. The normal eosinophil level is about 275/mm³, with anormal range of about 150-300/mm³. The normal monocyte level is about540/mm³, with a normal range of about 300-600/mm³. The normal adultplatelet level is about 2.5×10⁵/mm³, with a normal range of about2.1×10⁵-2.9×10⁵/mm³. The normal human adult red cell mass corresponds toabout 4.6×10¹² red cells/L in females and about 5.2×10¹² red cells/L inmales.

A human patient in need of treatment will typically have, or be subjectto developing, a cell count below these values. For example, the subjectmay have a cell count that is about 2% to about 90% below the lower orupper values of these ranges, e.g., about 5%, about 10%, about 20%,about 30%, about 50% or about 70% below any of these values. As usedherein, neutropenia means generally a circulating neutrophil count ofless than about 2000/mm³, typically less than about 1500/mm³ or usuallyless than about 1300/mm³. Under the common terminology criteria foradverse events, version 3.0, published at http://ctep.cancer.gov, grade1 neutropenia in humans is the lower limit of normal to 1500neutrophils/mm³, less than 1500 to 1000 neutrophils/mm³ is grade 2neutropenia, about 1000-500 neutrophils/mm³ is grade 3 neutropenia andless than about 500 neutrophils/mm³ is considered to be grade 4neutropenia. Febrile NP is NP accompanied by a fever, e.g., about 39.5°C. to about 43° C. or more, that is at least transient, e.g., lastingabout 2 or more hours.

Thrombocytopenia generally means a circulating platelet count of lessthan the normal circulating range, e.g., less than about 1.6×10⁵/mm³,less than about 1.5×10⁵/mm³, less than about 1.3×10⁵/mm³ or less thanabout 1.0×10⁵/mm³. Under the common terminology criteria for adverseevents, version 3.0, grade 1 thrombocytopenia is the lower normal limitto 75,000 platelets/mm³, grade 2 thrombocytopenia is <75,000-50,000platelets/mm³, grade 3 thrombocytopenia is <50,000-25,000 platelets/mm³and grade 4 is <25,000 platelets/mm³. Anemia generally means a red cellmass corresponding to less than about 4.0×10¹² red cells/L in adultfemales and less than about 4.5×10¹² red cells/L in adult males (ahemoglobin level of less than about 12.0 g/dL in adult females and lessthan about 13.5 g/dL in adult males).

In some cases, the diagnosis of a deficiency may cover a cell count thatfalls outside these ranges, due, e.g., to individual variations in asubject's age, sex, race, animal strain or normal blood cell status forthe individual. Such variations are identified by known means such as byidentification of a change from the subject's normal status or bymultiple cell measurements over time that reveal a deficiency. See,e.g., Hematology—Basic Principles and Practice, 2^(nd) edition, R.Hoffman, E. J. Benz Jr. et al., editors, Churchill Livingstone, N.Y.,1995. Subjects with an identified or identifiable deficiency outsidethese standard ranges are included in the definition of a blood celldeficiency or a subject in need of treatment, as used herein.

In exemplary embodiments, use of the F1Cs for treating subjectsincluding primates or humans who are subject to developing a NPcondition will typically result in a decreased in the severity and/orduration of NP. Typically, the F1C treatment will comprise treating thesubject daily, every other day or every third day for about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11 or 12 days with about 0.1 mg/kg to about 5 mg/kg,usually about 0.5 mg/kg to about 4 mg/kg. For these dosages, the F1C istypically administered by parenteral, e.g., intravenous, subcutaneous orintramuscular, or transmucosal delivery. Oral administration willgenerally use dosages that are about 3-25 mg/kg higher, e.g., about 4-30mg/kg of the F1C. Human unit dosages will typically comprise about1-1500 mg, usually about 10-150 mg, which can be subdivided, e.g., intotwo or three subdoses. Treatment of subjects who may develop a NPcondition from a chronic or slow onset condition will generally beginwhen reduced neutrophil counts are observed, e.g., when the subject hasgrade 1 or 2 NP. In situations where NP can arise over a short timeperiod, e.g., from an inducing event such as a chemotherapy, an acuteinfection or radiation exposure, treatment with the F1C will generallybegin at about the time of the inducing event. Thus, for subjects whowill be subjected a chemotherapy or radiation therapy, dosing with theF1C can begin about 1, 2, 3 or 4 days before, during (essentiallysimultaneous with or on the same day as) or about 1, 2, 3 or 4 after theinducing event. Typically dosing the F1C begins in a period from 2 daysbefore to 2 days after the subject is exposed to the NP inducing event.

Treatment with a F1C will reduce the severity of NP, e.g., by preventingthe development of grade 3 or 4 NP or febrile NP in subjects who wouldotherwise be expected to develop or susceptible to developing grade 3 or4 NP. The F1C will also typically reduce the duration of, e.g., grade 3or 4 NP, in subjects who would otherwise be expected to develop orsusceptible to developing such NP. The reduction in the duration of NP,grade 3 or 4 NP, can range from 100% to a detectable level, e.g., areduction of at least about 10%. Typically, the reduction of the periodduring which a subject has grade 3 or 4 NP or febrile NP is about 25% toabout 85%, e.g., about 30%, 40%, 50%, 60%, 70%, 80% or more.

Individual responses can vary depending on factors such as the subject'sinitial neutrophil status, when dosing with the F1C is initiated, dosageof the F1C and the route of administration of the F1C. NP in subjectssusceptible to developing NP can arise from conditions or treatments asdescribed herein, e.g., autoimmune conditions, cancer, cancerchemotherapy, an infection, antimicrobial chemotherapy, bone marrowtransplantion, an immunosuppressive therapy, bone marrow damage orexposure to or treatment with an ionizing radiation such as one or moreof γ-radiation, X-rays, fast neutrons, β-radiation or α-radiation.

TP, abnormally low platelet counts, can arise from impaired plateletproduction, sequestration of platelets in the spleen or abnormal loss ofcirculating platelets. Impaired production can result from causes suchas chemotherapy, radiation exposure, e.g., a radiation therapy, or anfrom autoimmune condition. Abnormal loss of circulating platelets isoften associated with autoreactive antibodies that bind to platelets andreduce their life span. These underlying causes give rise to the variousclinical forms of TP, such as autoimmune neonatal TP, immunethrombocytopenic purpura, radiation induced TP, chemotherapy induced TPand amegakaryocytic TP.

Other conditions that are amenable to prophylaxis or treatment by theinvention methods include the acquired blood cell deficiencies.Exemplary deficiencies or groups of deficiencies that can be treated areneonatal alloimmune TP, immune TP, immune thrombocytopenic purpura,thrombotic thrombocytopenic purpura, post-transfusion purpura, radiationassociated TP, chemotherapy associated TP (e.g., an anticancer,antiviral, antibacterial, antifungal or antiparasite therapy, NSAIDtreatments such as with indomethicin, ibuprofen, naproxen,phenylbutazone, piroxicam or zompirac, or β-lactam antibiotic treatmentssuch as with ampicillin, carbenicillin, penicillin G, ticarcillin, orcephalosporin treatments such as with cefazolin, cefoxitin orcephalothin, anticoagulant treatments such as heparin, hirudin,lepirudin or aspirin, treatment with plasma expanders or psychotropicdrugs), amegakaryocitic TP, radiation associated TP, TP associated withsolid organ allograft or xenograft rejection or immune suppressiontherapy in solid organ or other tissue transplants (e.g., liver, lung,kidney, heart, bone marrow, hematopoietic stem cell or endothelial celltransplant, implant or transfusion), cardiopulmonary bypass surgery,cardiovascular disease or therapy associated TP (e.g., congenitalcyanotic heart disease, valvular heart disease, pulmonary embolism,pulmonary hypertension disorders or diltiazem, nifedipine, nitroglycerinor nitroprusside therapy), TP associated with chronic or acute renalfailure or treatment for these conditions (e.g., dialysis), TPassociated with infection such as a virus or bacterial infection. NPconditions that can be treated include postinfectious NP, autoimmune NP,chronic idiopathic NP, basophilic leukopenia, eosinophilic leukopenia,monocytic leukopenia, neutrophilic leukopenia, cyclic NP, periodic NP,chemotherapy associated NP, radiation associated NP, NP associated withsolid organ allograft or xenograft rejection or immune suppressiontherapy in solid organ or other tissue transplants (e.g., liver, lung,kidney, heart, bone marrow, hematopoietic stem cell or endothelial celltransplant, implant or transfusion), chemotherapy associated leukopenia,radiation associated leukopenia, leukopenia associated with solid organallograft or xenograft rejection or immune suppression therapy in solidorgan or other tissue transplants (e.g., liver, lung, kidney, heart,bone marrow, hematopoietic stem cell or endothelial cell transplant,implant or transfusion), immune hemolytic anemias, anemia associatedwith chronic or acute renal failure or treatment for these conditions(e.g., dialysis), anemia associated with chemotherapy (e.g., isoniazid,prednisone) or anemia associated with radiation exposure.

The F1Cs are thus useful to facilitate or speed up immune systemrecovery in autologous bone marrow transplant or stem cell transplantsituations. In many cases it would be medically sound to continue thetreatment associated with causing or exacerbating the blood celldeficiency. Thus, in some embodiments a F1C treatment is conducted withsubjects who are undergoing another therapy at the same time or near thesame time, e.g., within about 1, 2, 3, 4 or several days to within about1-6 months. Such subjects typically will have an identified blood celldeficiency such as a NP or a TP, e.g., as disclosed herein. However, theF1Cs can be generally suitable for preventing the onset or reducing theseverity of such deficiencies, and they can thus be usedprophylactically in these indications, e.g., by administering a F1Cbeginning at about 1-60 days before administering another therapy thatcould lead to a cytopenia condition such as TP or NP.

In conditions such as NP, the F1Cs will typically function at least inpart by modulating, e.g., increasing, the level or activity ofbiomolecules such as IL-1β, G-CSF, GM-CSF or one or more of theirreceptors, that can enhance generation or survival of a desired celltype such as neutrophils. In this regard, the F1Cs can act as inducersof endogenous growth or differentiation factors that facilitateincreased production or survival of neutrophils or other blood celltypes. This aspect of the F1Cs allows one to eliminate or reduce the useof such molecules in treating conditions such as NP.

Use of a F1C in treating cytopenia conditions is thus optionallycombined with the use of an effective amount of one or more growthfactors or cytokines as a means to further enhance the effect of theF1Cs for their intended uses or to modulate, e.g., enhance, theireffects or efficacy. Suitable growth factors and cytokines are asdescribed herein or in the cited references. For example, when oneadministers the F1C to enhance generation of platelets in humans orother subjects, or their precursor cells such as CFU-blast cells,multipotent thymic precursor cells (CD34⁺, CD38⁺, CD7⁺, CD44⁺, CD33⁺,CD2⁻, CD5⁻, CD1a⁻), Pro-DC2 cells, immature DC2 cells, immature NKcells, CFU-GEMM, BFU-Mk, CFU-Mk, CFU-G, CFU-GM, immature megakaryocytesor mature postmitotic megakaryocytes, one can also administer one ormore of G-CSF, GM-CSF, SCF, Steel factor (“SF”), leukemia inhibitoryfactor (“LIF”), interkeukin-1α, (“IL-1α”), IL-3, IL-6, IL-11, TPO, EPO,their isoforms, their derivatives (e.g., linked to a PEG or fusions suchas PIXY321) or their isoforms, orthologs or homologs for other species.Similarly, administration of the F1C to enhance the generation orfunction of myelomonocytic cells such as neutrophils, basophils ormonocytes in humans or other subjects, can also be combined withadministration of one or more of G-CSF, GM-CSF, M-CSF, LIF, TPO, SF,interleukin-1 (“IL-1”), IL-2, IL-3, IL-4, interleukin-5 (“IL-5”), IL-6,IL-11, interleukin-12 (“IL-12”), interleukin-13 (“IL-13”), FLT3 ligand,their isoforms, orthologs, homologs or derivatives (e.g., linked to aPEG or fusions such as PIXY321) or their isoforms, orthologs or homologsfor other species. To enhance generation of red cells or their precursorcells such as CFU-GEMM, BFU-E or CFU-E in humans being treated with aF1C, one can co-administer one or more of G-CSF, GM-CSF, IL-1, IL-3,IL-6, TPO, EPO, transforming growth factor-ol, their isoforms, theirderivatives (e.g., linked to a PEG or fusions such as PIXY321) or theirisoforms, orthologs or homologs for other species. See, e.g.,Hematology—Basic Principles and Practice, 3^(rd) edition, R. Hoffman, E.J. Benz Jr. et al., editors, Churchill Livingstone, N.Y., 2000 (see,e.g., Chapters 14-17 at pages 154-260). The co-administration of suchfactors in these methods is intended to enhance the efficacy of the F1Ctreatment, which is optionally measured by taking suitable blood ortissue, e.g., bone marrow, samples at one or more times before and afterthe compounds have been administered. Such co-administration willgenerally be compatible with a subject's condition and other therapeutictreatments. Co-administration of such factors can precede, besimultaneous with, or follow the times of administration of the F1C(s)to the subject. Dosages of such growth factors would generally besimilar to those previously described, e.g., typically an initial courseof treatment comprises administering about 1.0 to about 20 μg/kg/d forabout 1-10 days, or as described in, e.g., Hematology—Basic Principlesand Practice, 3^(rd) edition, R. Hoffman, E. J. Benz Jr. et al.,editors, Churchill Livingstone, N.Y., 2000 (see, e.g., Chapter 51 atpages 939-979 and the references cited therein).

In cases where a subject's blood cell deficiency is caused by, orassociated with another therapy, the invention contemplates that theother therapy will continue, if this is reasonable under thecircumstances. The timing of other therapies can precede, besimultaneous with, or follow the times of administration of the F1C(s)to the subject. For example, chemotherapy for some malignancies isaccompanied by myelosuppression or a deficiency in one or more bloodcell types, e.g., TP or NP. Continued treatment would be called for insome cases, and then the invention methods would be employed to deliverto the subject an effective amount of a F1C. Thus, alkylating agents,antimicrotubule agents, antimetabolites, vinca alkaloids, topoisomeraseI or II inhibitors, or platinum compounds such as one or more ofmechlorethamine, vincristine, vinblastine, bleomycin, doxorubicin,epirubicin, tamoxifen, cyclophosphamide, etoposide, methotrexate,ifosfamide, melphalan, chlorambucil, busulfan, carmustine, lomustine,streptozocin, dacarbazine, vinorelbine, paclitaxel (taxol), docetaxel,cytosine arabinoside, hydroxyurea, fludarabine, 2′-chlorodeoxyadenosine,2′-deoxycoformycin, 6-thioguanine, 6-mercaptopurine, 5-azacytidine,gemcitabine, arabinofuranosylguanine, daunorubicin, mitoxantrone,amsacrine, topotecan, irinotecan, cisplatin, carboplatin, pilcamycin,procarbazine, aspariginase, aminoglutethimide, actinomycin D,azathioprine and gallium nitrate may be administered in conjunction withadministration of any F1C(s) that is disclosed herein. Treatments withother therapeutic agents such as heparin or nucleoside analogs such as3-thiacytosine, azidothymidine or dideoxycytosine, or otherantimicrobials such as cephalosporin, quinine, quinidine, gold salts(e.g., aurothioglucose), a fluoroquinolone (e.g., ciprofloxacin),clarithromycin, fluconazole, fusidic acid, gentamycin, nalidixic acid,penicillins, pentamidine, rifampicin, sulfa antibiotics, suramin orvancomycin may result in a blood cell deficiency(s) and they can thus becombined with administration of a F1C to treat the deficiency, or toameliorate a symptom thereof. Similarly, anti-inflammatory drugs (e.g.,salicylates, entanercept (a dimeric fusion comprising a portion of thehuman TNF receptor linked to the Fc portion of human IgG1 containing theC_(H)2 and C_(H)3 domain and hinge regions of IgG1) or a COX-2 inhibitorsuch as celexicob(4-5[-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzenesulfonamide)or rofecoxib (4-[4-methylsulfonyl)phenyl]-3-phenyl-2(5H)-furanone) or anIL-1 receptor antagonist such as anakinra), cardiac drugs (e.g.,digitoxin), β-blockers or antihypertensive drugs (e.g., oxprenolol orcaptopril), diuretics (e.g., spironolactone), benzodiazepines, (e.g.,diazepam) or antidepressants (e.g., amitriptyline, doxepin). Any ofthese methods also optionally include co-administration of one or moreof the growth factors described above, e.g., IL-3, G-CSF, GM-CSF or TPO.

Other therapies for treating a blood cytopenia such as TP or NP alsoinclude administering one or more of glucocorticoid steroids (e.g.,prednisone, prednisolone), human IgG antibodies, anti-Rh(D)⁺ antibodiesfor Rh(D)⁺ patients, an androgen such as danazol, vinca alkaloids (e.g.,vincristine, vinblastine), thrombopoietin and immunosuppresants (e.g.,azathioprine, cyclophosphamide, FK506 or cyclosporin). Splenectomy mayalso be indicated, for example when first line treatments fail. The goalof treatment for TP in humans is typically to increase platelet countsto at least about 20,000/mm³ or more typically to at least about50,000/mm³ and to maintain these levels.

Although the treatment options to increase platelet levels are generallyknown, they usually have a number of drawbacks. For example, infusion ofIgG antibodies is not always effective and the treatment is relativelyexpensive. Other treatments, such as prednisone are also not alwayseffective and they typically are discontinued or tapered off afterseveral weeks due to toxicity or unwanted side effects. Splenectomy,which is relatively expensive and invasive, is also not alwayseffective. The sources of thrombocytopenia and treatment options havebeen described. See, e.g., Hematology—Basic Principles and Practice,3^(rd) edition, R. Hoffman, E. J. Benz Jr. et al., editors, ChurchillLivingstone, N.Y., 2000 (see, e.g., Chapters 126-129 and 131 at pages2096-2154 and 2172-2186), PCT publication WO 200035466.

Neutropenia (“NP”), is considered to exist clinically when neutrophilsdrop to below a level considered normal. NP can arise from impairedproduction of neutrophil precursors or mature neutrophils, movement ofneutrophils from the circulation to tissue, abnormal circulatingneutrophil loss or a combination of these causes. Impaired neutrophilproduction can be acquired from, e.g., treatment with a cytotoxic orcytostatic drug, chemotherapy, radiation therapy or an autoimmuneresponse as described herein. The abnormal loss of circulatingneutrophils in autoimmunity is typically associated with autoreactiveantibodies that bind to the cells and reduce their life span. Theseunderlying causes give rise to the various clinical forms of NP, such aspostinfectious NP, drug-induced NP, autoimmune NP, or chronic idiopathicNP. The sources of NP and treatment options have been described. See,e.g., Hematology—Basic Principles and Practice, 3^(rd) edition, R.Hoffman, E. J. Benz Jr. et al., editors, Churchill Livingstone, N.Y.,2000 (see, e.g., Chapters 19, 41, 51, 79, 134 and 137 at pages 297-331,720-762, 939-979, 1443-1500, 2220-2248 and 2257-2263).

In some embodiments, the F1Cs that are used to enhance hematopoiesis orto treat associated conditions such as a TP or a NP disease or conditionas disclosed herein, are characterized by having a lack of appreciableandrogenicity. In these embodiments, the F1Cs are characterized byhaving about 15% or less, about 10% or less, about 5% or less, about 2%or less, about 1% or less or about 0.5% or less of the androgenicity ofa reference androgen such as testosterone, testosterone proprionate,dihydrotestosterone or dihydrotestosterone proprionate as measured in asuitable assay using suitable positive and/or negative controls. F1Cshaving, e.g., a substitution at the 6- or 7-position or having no doublebond at the 4-5 or 5-6 positions, will generally have relatively lowlevels of androgen activity. Suitable assays for androgenicity ofvarious compounds have been described, e.g., J. R. Brooks, et al.,Prostate 1991, 18:215-227, M. Gerrity et al., Int. J. Androl. 19814:494-504, S. S. Rao et al., Indian J. Exp. Biol. 1969 7:20-22, O.Sunami et al., J. Toxicol. Sci. 2000 25:403-415, G. H. Deckers et al.,J. Steroid Biochem. Mol. Biol. 2000 74:83-92. The androgenicity of theF1Cs are optionally determined as described or essentially as describedin one or more of these assays or any other assay. Thus, one suchembodiment comprises a method to enhance hematopoiesis or to treat TP orNP comprising administering to a subject in need thereof an effectiveamount of a F1C, or delivering to the subject's tissues an effectiveamount of a F1C, wherein the F1C has about 30% or less, about 20% orless, about 10% or less or about 5% or less of the androgenicity of anandrogen such as testosterone, testosterone proprionate,dihydrotestosterone or dihydrotestosterone proprionate as measured in asuitable assay, e.g., as described in the citations above. In conductingsuch methods, the subjects, e.g., rodents, humans or primates, areoptionally monitored for e.g., amelioration, prevention or a reducedseverity of a disease, condition or symptom. Such monitoring canoptionally include measuring one or more of cytokines (e.g., TNFα,IL-1β), WBCs, platelets, granulocytes, neutrophils, RBCs, NK cells,macrophages or other immune cell types, e.g., as described herein or inthe cited references, in circulation at suitable times, e.g., atbaseline before treatment is started and at various times during orafter treatment with a F1C, e.g., at about 2-45 days after treatmentwith a F1C has ended.

In conducting any of these methods, one can monitor the subject'sclinical condition at any relevant time before, during or afteradministration of the F1Cs, which treatments are optionally combinedwith any of the other agents or treatments described above. Thesubject's blood can be drawn on one, two or more occasions in advance oftreatment to, e.g., obtain a baseline or initial level of white or redblood cells, to verify a presumptive diagnosis of a blood celldeficiency or to determine a blood parameter such as circulatingmyelomonocyte counts, circulating neutrophil counts or circulatingplatelet counts. Then, during the course of treatment or thereafter thesubject's blood can be drawn on one, two or more occasions to follow thesubject's response, e.g., once treatment with a F1C has ended.

Invention embodiments include methods that comprise administering to asubject in need thereof an effective amount of a F1C and an effectiveamount of at least one form of interferon, such as γ-Interferon or agrowth factor or interleukin such as G-CSF or IL-6. Interferons canenhance the biological activity of the white cells that arise fromincreased hematopoiesis. This can be particularly useful when thesubject's circulating blood cell deficiency is associated with, e.g., aninfection or a chemotherapy that suppresses hematopoiesis.Administration of a growth factor or an interleukin such as IL-6 canfacilitate hematopoiesis by stimulating quiescent stem cells or otherprogenitors that give rise to deficient cell types. Related embodimentsreplace growth factor or interferon administration partially orcompletely by increasing endogenous production in the subject usingconventional methods, e.g., administering double stranded RNA tostimulate Y-IFN.

In these embodiments, the subject may have thrombocytopenia orneutropenia or the subject's circulating platelets, red cells, maturemyelomonocytic cells, or their precursor cells, in circulation or intissue may be detectably increased. In some cases the subject has renalfailure. These methods may further comprise the steps of obtaining bloodfrom the subject before administration of the F1C and measuring thesubject's white or red cell counts and optionally, on one, two, three ormore occasions, measuring the subject's circulating white cell or redcell counts after administration of the F1C, e.g., within about 12 weeksafter an initial administration of a F1C or during or within about 12weeks after a course of treatment as described herein.

Delayed radiation effects. Invention embodiments include a method toprevent, treat or ameliorate a symptom or condition associated with oneor more delayed adverse effect, symptom or condition from ionizingradiation exposure in a subject in need thereof comprising administeringto the subject, or delivering to the subject's tissues, an effectiveamount of a F1C. In these embodiments, administration of the F1Ccommences at least 2 weeks after the subject has been exposed to a doseor subdose of radiation that could give rise to a delayed radiationeffect. Dosing with the F1C can thus begin at 14 days to about 2 yearsor more after ionizing radiation exposure. Typically dosing will beginat about 2 weeks, 3 weeks, or 1, 2, 3 or 4 months after exposure of thesubject to sufficient ionizing radiation to potentially cause delayedeffects. Radiation exposure may arise from a radiation therapy whereexposure is intentional, or it may arise from an accidental exposure.

Radiation therapy (“RT”) can generate a number of late delayed-onsetconditions or symptoms. Delayed radiation effects are conditions orsymptoms that generally arise or become detectable to the subject or toa health care provider at least about 1 month after exposure toradiation. Thus the conditions or symptoms may be detectable at about 2months, about 3 months, about 4 months, about 5 months, about 1 year,about 20 years or more after radiation exposure. For example, transientnervous system symptoms may develop early after RT, but progressive,permanent, often disabling nervous system damage may appear months oryears later. The total radiation dose, size of the fractions, durationof RT, and volume of tissue irradiated influence the probability of theinjury and its severity. Individual patient and tissue susceptibility todelayed injuries is variable, which factors into the selection of safeand effective radiation doses for RT. Total radiation doses that asubject may receive may comprise single doses or 2, 3, 4, or more doseswithin a range of about 1 to about 400 Gy, e.g., about 1, 1.4, 1.6, 1.8,2, 2.5, 3, 5, 10, 20, 40, 50, 80, 100, 130, 150, 180, 200, 250, 300, 400Gy. Typical doses are about 1-12 Gy or about 1-8 Gy. Such doses in agiven course of treatment may be the same or different and can occurover a period of time, e.g., over 1 day to about 1 or 2 years.

In some embodiments, the total radiation dose occurs on a singleexposure that occurs in a relatively short time period, e.g., about 1-20minutes to about 12 hours. In other embodiments, the total dose isdelivered to the subject in multiple doses or over a longer time, e.g.,over about 2 days to about 12 months or more in multiple doses in, e.g.,2, 3, 4, 6, 8, 10 or more individual doses. Ameliorating a side effectmay comprise detectably slowing the progression of a symptom orcondition or detectably reducing the ultimate expected severity of asymptom or condition. The affected condition or symptom may bedetectably reduced as determined by the subject or the health careprovider. Thus, after administration of a F1C, the target symptom orcondition may be moderately reduced, slightly reduced, essentiallynonexistent or subclinical, e.g., present at a low level that is notdeemed significant by the subject or the health care provider.Amelioration of one or more conditions or symptoms that can be suitablyquantified may be observed as a decrease of about 5% or more, e.g., atleast about 10%, at least about 20%, at least about 30%, at least about40%, at least about 50%, at least about 70%, at least about 80% or atleast about 90% in the relative expected or potential severity or extentof the condition or symptom.

For example, in lung pneumonitis, administration of a F1C can lead todetectably increased oxygen saturation in the subject's blood by about5% or by about 10% or more, e.g., oxygen saturation can rise from about83% to about 88%, which would typically be detectable by the subject andthe health care provider. Such decreased severity of a condition orsymptom may be objectively measured in some instances, e.g., bydetermining the number or activity of circulating platelets orneutrophils or by evaluation of fever, severity or frequency of diarrheaor blood oxygen saturation levels. For other symptoms or conditions,prevention may be subjectively observed by a significant or detectableimprovement in a relevant score, e.g., decreased fever or pain or adecreased need for treatment of fever, pain or inflammation.

Symptoms or conditions of radiation exposure that can be treated alsoinclude encephalopathy, myelopathy, nausea, diarrhea, acuteinflammation, chronic inflammation, edema, pain, fever, headache,depression, malaise, weakness, hair loss, skin atrophy, skin ulceration,skin lesion, keratosis, telangiectasia, infection, e.g., bacterial,viral, fungal or yeast infection, hypoplasia, atrophy, marrowhypoplasia, hemorrhage, fibrosis, e.g., lung fibrosis, pneumonitis, bonemarrow hypoplasia, hemorrhage or cytopenia, e.g., anemia, leukopenia orthrombocytopenia, edema, fibrosis or hemorrhage or the need for edema,fibrosis or hemorrhage treatment. Such symptoms or conditions may arisefrom one or more radiation-damaged tissues or cells, including lymphoidcells, bowel or intestinal epithelium or tissue, bone marrow, testicles,ovaries, brain tissue, spinal cord tissue or skin epithelium.

Exemplary symptoms or conditions associated with late effects ofradiation exposure include (1) acute or chronic radiation-inducedenteritis or diarrhea, e.g., in patients receiving pelvic radiotherapy,(2) pseudomembranous inflammation, (3) perivascular fibrosis, (4)endothelial cell damage or death, e.g., associated with vascularradiation therapy, (5) cardiac tissue inflammation or damage orpericardial disease, e.g., in pediatric or adult patients receivingradiation therapy for a leukemia, thoracic neoplasm or other malignancy,(6) pulmonary tissue inflammation or damage, (7) hematopoietic or marrowcell inflammation or damage, e.g., in wide field radiation therapy, (8)endocrine or thyroid dysfunction, e.g., in thalamic or hypothalamictumors in pediatric or other patients, (9) decreased growth or decreasedbone development or density, e.g., in pediatric patients receivingradiation therapy for a childhood leukemia or other malignancy, (10)central nervous system inflammation or damage, e.g., in pediatric oradult patients receiving radiation therapy for a leukemia (e.g., CNSacute lymphocytic leukemia) or other malignancy, (11) connective tissuedamage after radiation therapy, (12) incidence or severity of asecondary leukemia such as acute myelogenous leukemia or myelodysplasiaand (13) gastric ulceration, bleeding, small bowel obstruction orfistula formation in, e.g., patients receiving radiation therapy to thegastrointestinal tract. These symptoms or conditions are treated orameliorated using the F1Cs essentially as disclosed herein.

In treating such symptoms or conditions, slowing the progression of asymptom, condition or side effect will detectably reduce the rate atwhich the condition, symptom or side effect worsens or intensifies. Insome embodiments, pronounced slowing of the rate of progression is,e.g., the time needed to progress to an expected or a measurable point,which may be increased by a period of about 1, 2, 3, 4, 5, 10, 20, 30 ormore days to a period of about 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 36, 48,72 or more months.

Radiation-associated brain damage can give rise to acute encephalopathywith symptoms such as headache, nausea, vomiting, somnolence,depression, disorientation, and worsening neurologic signs. Theencephalopathy may arise from the first, second or a subsequentradiation fraction, e.g., when high intracranial pressure has not beentreated with, e.g., corticosteroids. Late-delayed radiation damage tothe brain or nervous system can arise at about 2, 3, 4, 5, 6, 7, 8, 9,or 10 months to 1, 2, 3 or more years after leukemia prophylaxis inchildren or after brain tumor prophylaxis or treatment in adults.Symptoms often include pain or headache and progressive dementia withoutfocal signs and adults typically also develop an unsteady gait. Cerebralatrophy appears on CT scans in some cases. Late-delayed damage can ariseat about 1 week, about 2 weeks about 2 months or about 1-2 years afterirradiation of extracranial tumors or high-dose irradiation ofintracranial tumors, e.g., brachytherapy or radiosurgery, although thesymptoms are generally more focal. The invention method would be usedduring the time period when such symptoms would be expected to arise,e.g., commencing at about 1-5 days or about 7-60 days after radiationexposure and ending at about 0.5, 1, 2, 3, 4, 5 or more years later.Exemplary brachytherapies and unsealed source therapies include prostate¹²⁵I seed implants in prostate conditions such as prostate cancer, ⁹⁰Ytconjugated to monoclonal antibodies or in endovascular brachialradiotherapy.

Early-delayed radiation spinal cord myelopathy follows radiation therapyto the spinal cord, neck, upper thorax or lumbar region or and it isoften characterized by Lhermitte's sign, i.e., an electric shock-likesensation radiating down the back and into the legs on neck flexion.Late-delayed radiation myelopathy can arise months or years aftertherapy for extraspinal tumors, e.g., Hodgkin's disease. Other symptomscan include progressive weakness and sensory loss, such as aBrown-Sequard type, i.e., a proprioceptive sensory loss and weakness onone side of the body and loss of temperature and pain sensation on theother side. Progression times vary, but many human patients sufferingfrom late-delayed radiation spinal cord myelopathy become paraplegic.Late-delayed radiation neuropathy may produce brachial neuropathy, e.g.,after treatment for breast or lung cancer. Radiation can also give riseto gliomas, meningiomas, or peripheral nerve sheath tumors at about 1,2, 3, 4, 5 or more years after therapy. The F1Cs will generally beadministered at about the time period when these symptoms would beexpected to arise, e.g., commencing at about 1-5 days, or about 7-60days or about 6 or 12 months after radiation exposure and ending atabout 3, 4, 6 months later or about 1, 2, 3, 4, 5, 6 or more yearslater. In some embodiments, the F1C is administered to the subject onthe same day that a planned or accidental radiation exposure occurs anddosing is continued for about 1, 2, 3, 4, 8, 12 or more weeks to about2, 3, 4, 5, 6 or more years, or for a time as disclosed elsewhereherein.

Early-delayed encephalopathy often arises or is detectable at about 2, 3or 4 months after radiation therapy. This encephalopathy in adults, isdistinguished from worsening or recurrent brain tumor by, e.g., computedtomography (CT) or magnetic resonance imaging (MRI). The condition inchildren can occur as a somnolence syndrome, e.g., after whole-brainirradiation for leukemia. The condition in children typically improvesspontaneously over several days to weeks. Such encephalopathies can beprevented, delayed in onset, recede more rapidly and/or be less severewhen a F1C is administered to the subject throughout the period whenencephalopathy can arise, e.g., beginning about a week, two weeks or amonth before the expected onset of a symptom or condition and endingabout a week or month or two months after it would be expected to ariseor to resolve.

In some embodiments, a radiation late effect is a symptom or conditionthat may arise months or years after radiation exposure, treatment withthe F1C can commence shortly, e.g., about 0.5, 1, 2, 3, 4, 5, 10, 14, 21or 28 days, after the radiation exposure or after initiation of aradiation treatment. In other embodiments, the invention treatmentmethod can commence after radiation exposure has terminated, e.g., about1-30 days or about 1-72 months or more after radiation exposure. Inthese embodiments, the treatment method can be administered over aperiod of months or years, e.g., about 0.5, 1, 2, 3, 4, 5, 6, 12, 18,24, 36, 48, 72, 96 or more months. In some embodiments, dosing of thesubject will occur for a period of about 2-12 months or for a period ofabout 4-6 months. Occasionally, treatment for radiation late effectswill commence on the day of or before initiation of a planned radiationtreatment, e.g., at about 1, 2, 3, 4, 5, 7, 14, 21, 28 or more daysbefore a planned exposure to radiation of a sufficient dose to a subjectthat will potentially generate, or is likely to generate, one or moreradiation late effects, symptoms or conditions in the subject, e.g., anyradiation-associated symptom or condition disclosed herein. In any ofthese embodiments, dosing of the subject with the F1C can be on a dailydosing basis or on an intermittent basis, e.g., using a treatmentprotocol essentially as described herein or in the cited references.

The F1Cs can be used to prevent, ameliorate, slow the progression and/orreduce the ultimate severity of marrow hypoplasia, hemorrhage, e.g.,brainstem hemorrhage, cerebral hemorrhage or gastric hemorrhage orcytopenia, e.g., a blood cell count about 4-25% or more below the lowend of a normal range for the subject, e.g., one or more of anemia(e.g., less than about 4.0×10¹² red cells/L for adult human females andless than about 4.5×10¹² red cells/L in adult human males or ahemoglobin level of less than about 12.0 g/dL in adult human females andless than about 13.5 g/dL in adult human males), late effect leukopenia(e.g., adult human white blood cell counts less than about 3,800, 4,000or 4,300 mm⁻³; adult human basophil counts less than about 10 or 15mm⁻³; adult human neutrophil counts less than about 1,600, 1,800 or2,000 mm⁻³; human eosinophil level less than about 100, 120 or 150 mm⁻³;monocyte level less than about 260 or 300 mm⁻³) or late effectthrombocytopenia (e.g., human platelet counts less than about 15,000,18,000 or 20,000 mm⁻³).

In some embodiments, an effective amount of a F1C is administered to asubject, or delivered to the subject's tissues, wherein the subject hasreceived or has been exposed to a total radiation dose of at least about0.5 Gy to about 100 Gy or more. The radiation dosage may comprise asingle dose or two, three, four, five, six, 10 or more divided doses orsubdoses. Thus, in exemplary embodiments, the subject may have receiveda total radiation dose in ranges of about 0.2-300 Gy, about 0.2-100 Gy,about 0.2-80 Gy 0.2-60 Gy, about 0.2-40 Gy, about 0.2-20 Gy, about0.2-12 Gy, about 0.2-10 Gy, about 0.2-8 Gy, about 0.2-6 Gy or about0.2-4 Gy. Subdivided doses may be administered on 1, 2, 3, 4, 5, 6, 7,8, 9, 10 or more occasions and such doses may be, e.g., about 0.05, 0.1,0.3, 0.5, 0.8, 1, 2, 3, 4, 5, 6 or more Gy per subdose. The subject maybe exposed to radiation subdoses over a period of about one day or overseveral days, e.g., about 2, 3, 4, 5, 6, 8, 10, 20 or 25 days, or over aperiod of months, e.g., about 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 18, 24,36, 48 or more months. When a subject is exposed to a full dose or asubdose of radiation, the exposure will occur over a period of about 1minute to about 48 hours, typically about 2-120 minutes or about 4-60minutes. Radiation doses or subdoses may be, e.g., about 0.01, 0.05,0.1, 0.2, 0.5, 0.8, 1, 1.5, 2, 2.5, 3, 4, 5, 6 or 8 Gy per dose orsubdose.

Administration of the F1C will typically commence at about 1 day toabout 6 months after a subject has received a total radiation exposure,e.g., any dose or dose range disclosed herein. Typically, the F1C isused in the invention method commencing at about 2-120 days afterradiation exposure or at about the time that radiation delayed effectsbecome apparent to the subject or the subject's health care provider,e.g., within about 1-30 days after a condition or symptom is detected.Administration of the F1C may continue for a period of about 5 days toabout 60 days for conditions or symptoms that tend to resolve over arelatively short time period. In other embodiments, the F1C isadministered for a period of 2, 3, 4, 5, 6, 8, 10, 12, 15, 18, 24, 36,48, 60 or more months for conditions or symptoms that tend to be chronic(e.g., neurological damage or inflammation), arise over a long timeperiod (e.g., secondary cancers or neurological damage) or to progressover a relatively long time, e.g., about 1-5 years or more (e.g.,cancers or neurological damage).

In any of the radiation exposure embodiments or dosing protocolsdisclosed herein, the F1C can be administered to the subject daily or onan intermittent basis, e.g., on about 1-5 days/week or about 2-10days/month. In daily dosing embodiments, the F1C is administered to thesubject daily for about 3 days to about 5 years or longer. Exemplarydaily dosing embodiments include daily administration of a F1C for about14, 30, 60, 90, 120, 180, 360 or more days. Daily doses may beadministered in a single dose or as divided subdoses that are given,e.g., twice, three times, four times or more per day. In intermittentdosing embodiments, the F1C can be administered to the subject on 1, 2,3, 4 or 5 days within a one week period, followed by a period of about1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 20, 24, 28 or 32 weeks withoutadministration of the F1C, followed by administration of the F1C to thesubject on 1, 2, 3, 4 or 5 days within a one week period. In otherintermittent dosing embodiments, the F1C is administered to the subjectevery other day, every two days, every three days, every 4 days or everyseven days.

For any radiation exposure situation where delayed radiation effects mayarise, e.g., a radiation exposure as disclosed herein, dailyadministration may comprise administering about 0.01 mg/kg to about 500mg/kg of the F1C to a subject per day. Exemplary dosages are about0.1-100 mg/kg/day and about 0.2-30 mg/kg/day. Exemplary unit dosescomprise about 1, 5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 200, 300 or500 mg of a F1C in a suitable formulation. Exemplary unit dosages forhumans or other subjects disclosed herein comprise a formulation thatcomprises about 1-1000 mg of a F1C or about 5-400 mg or about 10-300 mg,e.g., about 5, 10, 20, 25, 30, 40, 50, 60 75, 100, 150, 200, 250, 300,400 or 500 mg. Larger unit or daily dosages, e.g., about 5-400 mg, willgenerally be used with larger subjects such as humans, while smallersubjects such as rodents or dogs will generally utilize lower unit ordaily dosages, e.g., about 0.3-25 mg.

Modulation of transcription factors, receptors and gene expression. Intreating any of the diseases, conditions or symptoms disclosed herein,the F1Cs can modulate, i.e., detectably enhance or increase ordetectably inhibit or decrease, the expression or a biologicalactivity(ies) of one or more transcription factors or receptors. Thiscan lead to detectable modulation of target gene activity or expressionas part of the treatment or amelioration of the disease, condition orsymptom. Such modulation can arise from changes in the capacity of atranscription factor or receptor to bind to or form a complex with othernatural ligands such as a target DNA sequence(s), another transcriptionfactor(s), a transcription cofactor, a receptor such as a nuclearhormone receptor or cell membrane receptor (e.g., a lipid, peptide,protein or glycoprotein receptor such as an interleukin receptor or agrowth factor receptor), a receptor cofactor or an enzyme such as apolymerase, kinase, phosphatase or transferase. The effects of F1Cs onthese biomolecules can be exerted in immune cells or in non-immunetissue, e.g., cells or tissue adjacent to diseased tissue such asinfected or malignant cells. The F1Cs may directly or indirectlymodulate the capacity of any of these molecules to transduce signalsthat are part of normal signal transduction processes.

In many of the clinical conditions described herein, e.g., in cancers,infections, acute inflammation, chronic inflammation, trauma,neurological conditions or autoimmunity, the F1Cs can modulate, e.g.,detectably decrease or increase, a biological activity(ies), protein ormolecule level or RNA level of 1, 2, 3, 4, 5, 6 or more biomoleculesthat are involved in establishment, maintenance or progression of adisease, condition or symptom. Such biomolecules include 1, 2, 3, 4, 5,6 or more of AP-1, a cyclooxygenase such as mammalian or humancyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2), a mammalian orhuman lipoxygenase, e.g., 5-lipoxygenase, TNFα, TNFα receptor 1, TNFαreceptor 2, TNF receptor-associated factor, TNFβ, TNFβ receptor, MIP-1α,monocyte chemoattractant-1 (MCP-1), interferon gamma (IFNγ or γIFN),IL-1α, IL-1β, IL-1α receptor, IL-1β receptor, IL-2, IL-3, IL-4, IL-4receptor (IL-4R), IL-5, IL-6, IL-6 receptor (IL-6R), IL-8, IL-8 receptor(IL-8R), IL-10, IL-10 receptor (IL-10R), IL-12, an IL-12 receptor,(e.g., IL-12Rβ2), IL-13, IL-15, IL-17, IL-18, nuclear factor kappa B(NFκB), AP-1, c-maf, v-maf, mafB, NrI, mafK, mafG, the maf familyprotein p18, reactive oxygen species, e.g., peroxynitrite, hydrogenperoxide or superoxide ion (collectively ROS), a 17β-hydroxysteroiddehydrogenase (17β-HSD) or an 11β-hydroxysteroid dehydrogenase(11β-HSD), e.g., 11β-HSD type 1, 11β-HSD type 2, 17β-HSD type 1, 17β-HSDtype 2 or 17β-HSD type 5, a steroid aromatase, e.g., cytochrome P450aromatase, steroid 5α-reductase, serum or blood cortisol, cytosolicphospholipase A2 (cPLA2), calcium-independent phospholipase A2 (iPLA2),a prostaglandin, e.g., prostaglandin E2 (PGE2) or prostaglandin D2(PGD2), a leukotriene, e.g., leukotriene B4, inducible nitric oxidesynthetase (iNOS), nitric oxide (NO), GM-CSF, RANTES (regulated onactivation, normal T cells expressed and secreted), eotaxin, GATA-3,CCR1, CCR3, CCR4, CCR5, CXCR4, in, e.g., a subject's cell(s) ortissue(s) or in enzyme, tissue or cell-based assays. In these subjects,the levels of other biomolecules, their RNAs or the level of theiractivity can be detectably modulated include IFNα, INFα receptor, PPARα,PPARγ, PPARδ or a transcription factor such as T-bet is detectablyincreased. Other biomolecules or their isoforms, polymorphs, orthologs,or homologs that the F1Cs directly or indirectly modulate include one ormore of, e.g., Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Januskinase 3 (JAK3), signal transducer and activator of transcription 1(STAT1), signal transducer and activator of transcription 2 (STAT2) andsignal transducer and activator of transcription 3 (STAT3). The F1Cs canmodulate the other biologically active analogs of any these enzymes,chemokines, cytokines, their receptors or ligands, including theirisoforms, polymorphs, orthologs or homologs. In some cells or tissues,one or more of these biomolecules may be detectably increased, while inother cells or tissues, the same biomolecule may be detectablydecreased. Thus, the biomolecules that the F1Cs can modulate, e.g.,detectably increase or decrease, include the intracellular orextracellular level or biological activity of one or more enzyme,cytokine, cytokine receptor, chemokine and/or chemokine receptor.Exemplary chemokine receptors include one, two or more of CCR-1, CCR-2,CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3 and CXCR-4.

The F1Cs can modulate the activity of certain biomolecules that mediatevarious biological responses that affect establishment or progression ofa disease or that enhance or inhibit specific immune responses. Thus, inconditions where unwanted inflammation is present, the F1Cs can reduceinflammation, while enhancing Th1 or Tc1 immune responses at the sametime. The biomolecules that the F1Cs can modulate include, e.g.,transcription factors or receptors, including orphan nuclear receptors,and the homologs, isoforms, orthologs and co-factors (e.g.,co-repressors, co-activators, transcription factors, gene promoterregions, sequences or messenger moieties such as calcium ions, potassiumions or cAMP) of any of these molecules and related molecules thatparticipate in their function. The compounds can directly or indirectlyfrom complexes with such molecules or they can modulate (detectablyincrease or decrease) the synthesis, level or one or more biologicalactivities of those molecules. These complexes include receptors ortranscription factor complexes, which can comprise heterodimers,homodimers and trimer, tetramer, pentamer or higher homo or heterocomplexes. A number of the orphan receptors or their isoforms, orthologsor homologs, e.g., PPARα, PPARβ, PPARγ, PPARγ1, PPARγ2, PPARγ3, LXRα,LXRβ, SXR, PXR, CARα and CARβ, can form heterodimers with one or more ofRXRα, RXRβ and RXRγ. Exemplary mammalian, human or other biomoleculesinclude steroidogenic factor-1 (SF-1), steroidogenic acute regulatoryprotein (StAR), a chicken ovalbumin upstream promoter-transcriptionfactor (COUP-TF), chicken ovalbumin upstream promoter-transcriptionfactor (COUP-TFI) and its mammalian isoforms, orthologs and homologs,silencing mediator for retinoid and thyroid hormone receptor (SMRT) andits mammalian isoforms, orthologs and homologs, sterol regulatoryelement binding protein (SREBP) 1a (SREBP-1a), SREBP-1c, SREPB-2, NF-E3,FKHR-L1, COUP-TFII and its mammalian isoforms, orthologs and homologs,and the isoforms, orthologs and homologs of IκB, IκBα, AML-3, PEBP2αA1,Osf2, Cbfa1, RUNX2, activating transcription factor 2 (ATF2), c-Jun,c-Fos, a mitogen activated kinase (MAP) such as p38 or JNK, a mitogenactivated kinase kinase (MKK), a p160 or steroid receptor coactivator-1family (SRC-1, SRC-1/serum response factor), SRC-2, SRC-3, SET, nervegrowth factor inducible protein B, StF-IT, NFAT, NFAT interactingprotein 45 (NIP45), IkB, an IkB kinase, NFATp, NFAT4, an AP-1 familyprotein, a p300 protein, CREB, CREB-binding protein (CPB), p300/CBP,p300/CPB-associated factor, SWI/SNF and their human and other homologs,BRG-1, OCT-1/OAF, AP-1, AF-2, Ets, androgen receptor associated protein54 (ARA54), androgen receptor associated protein 55 (ARA55), androgenreceptor associated protein 70 (ARA70), androgen receptor-interactingprotein 3 (ARIP3), ARIP3/PIASx α complex, PIASx α, Miz1, Miz1/PIASx βcomplex, PIASx β, PIAS1, PIAS3, GBP, GBP/PIAS1 complex, RAC3/ACTRcomplex, SRC-1α, receptor interacting protein-140 (RIP-140),transcription factor activator protein-1, activation function-2,glucocorticoid receptor-interacting protein-1 (GRIP-1), receptorinteracting protein-160 (RIP-160), suppressor of gal4D lesions (SUG-1),transcription intermediary factor-1 (TIF-1), transcription intermediaryfactor-2 (TIF-2), SMRT, N-CoR, N-CoA-1, p/CIP, p65 (RelA), the 120 KDrel-related transcription factor, heat shock proteins (HSP) such asHSP90, HSP70 and HSP72, heat shock factor-1, Vpr encoded by the humanimmunodeficiency virus and its isoforms and homologs thereof, testicularorphan receptor 2 (TR2), testicular orphan receptor 4 (TR4), a thyroidhormone receptor α, thyroid hormone receptor α1 (TRα1), thyroid hormonereceptor α2 (TRα2), thyroid hormone receptor β (TRβ), retinoid Xreceptor α (RXRα), retinoid X receptor β (RXRβ), retinoid X receptor γ(RXRγ), TR α1/RXR α heterodimer, direct repeat-4 thyroid hormoneresponse element (DR4-TRE), an estrogen receptor (ER) such as ERα orERβ, estrogen receptor related receptor α (ERRα or EER1), estrogenreceptor related receptor β (ERRβ or EER2), estrogen receptor relatedreceptor γ (ERRγ or EER3), steroid xenobiotic receptor (SXR), ahepatocyte nuclear factor 4 (HNF-4), hepatocyte nuclear factor 4γ(HNF-4γ), hepatocyte nuclear factor 3 (HNF-3), liver X receptors (LXRs),LXRα, LXRβ, estrogen receptor α (ERα), constitutive androstanereceptor-α (CAR-α), constitutive androstane receptor-β (CAR-β),RXR/CAR-β heterodimer, short heterodimer partner (SHP; NR0B2), SHP/ERαheterodimer, estrogen receptor β, SHP/ERβ heterodimer, testicular orphanreceptor TR4, TR2/TR4 heterodimer, pregnane X receptor (PXR) andisoforms, cytochrome P-450 monooxygenase 3A4, including its genepromoter region and isoforms thereof, HNF-4/cytochrome P-450monooxygenase 3A4 gene promoter region and isoforms complex, HIV-1 longterminal repeat (LTR), HIV-2 LTR, TR2/HIV-1 LTR complex, TR4/HIV-1 LTRcomplex, TR4/HIV-1 LTR complex, TR α1/TR4/HIV-1 LTR complex, TR2isoforms (TR2-5, TR7, TR9, TR11), DAX-1 (NR0B1), DAX-1/steroidogenicacute regulatory protein gene promoter region, RevErb, Rev-erbA α,Rev-erb β, steroid receptor coactivator amplified in breast cancer (AIB1), p300/CREB binding protein-interacting protein (p/CIP), thyroidhormone receptor (TR, T3R), thyroid hormone response elements (T3RES),retinoblastoma protein (Rb), tumor suppressor factor p53, transcriptionfactor E2F, mammalian acute phase response factor (APRF), constitutiveandrostane receptor (CAR), Xenopus xSRC-3 and mammalian (e.g., human)isoforms, orthologs and homologs, TAK1, TAK1/peroxisomeproliferator-activated receptor α (PPARα) complex, PPARα/RXRα complex,peroxisome proliferator-activated receptor β (PPARβ), peroxisomeproliferator-activated receptor γ (PPARγ), peroxisomeproliferator-activated receptor δ (PPARδ), farnesoid X receptor, retinaX receptor, TAK-1/RIP-140 complex, a retinoic acid receptor (RAR),retinoic acid receptor-β (RARβ), retinoic acid receptors (RARγ),TR4/RXRE complex, SF-1/steroid hydroxylase gene promoter region,SF-1/oxytocin, including its gene promoter region, a bile acid receptor(FXR), nuclear receptor corepressor (NcoR), liver receptor homologousprotein-1 (LRH-1; NR5A2), SF-1/ACTH receptor gene promoter region, ratEar-2 and mammalian homologs, human TR3 orphan receptor (TR3), RLD-1,OR-1, androgen receptor, glucocorticoid receptor, estrogen receptor,progesterone receptor, mineralcorticoid receptor, aldosterone receptor,E6-associated protein (E6-AP), OR1, OR1/RXRα complex, TIF-1, CBP/P300complex, TRIP1/SUG-1 complex, RIP-140, steroid receptor coactivator 1(SRC1), SRC1α/P160 complex and TIF-2/GRIP-1 complex, RAR/N-CoR/RIP13complex, RAR/SMRT/TRAC-2 complex and protein X of hepatitis B virus. Thehomologs, orthologs and isoforms of these transcription factors,receptors and other molecules are included among the molecules that theF1Cs can modulate the synthesis or one or more biological activities of.Such factors are biologically active or function in one or more of anumber of cell types such as T cells, B cells, macrophages, dendriticcells, platelets, monocytes, neutrophils, neurons, epithelial cells,endothelial cells, cartilage cells, osteoblasts, osteoclasts,splenocytes, thymocytes and GALT associated cells. Methods to identifythese molecules and their biological activities have been described,e.g., U.S. Pat. Nos. 6,248,781, 6,242,253, 6,180,681, 6,174,676,6,090,561, 6,090,542, 6,074,850, 6,063,583, 6,051,373, 6,024,940,5,989,810, 5,958,671, 5,925,657, 5,958,671, 5,844,082, 5,837,840,5,770,581, 5,756,673, and PCT publication Nos. WO 00/24245, WO 0073453and WO 97/39721.

In one aspect, the compounds are used to treat, prevent or to ameliorateconditions or symptoms that are associated with unwanted or expressionor activity of one or more of these molecules in conditions such as,e.g., acute inflammation, chronic inflammation or their symptoms, acuteallergy, chronic allergy or their symptoms, e.g., allergic rhinitis oracute or chronic asthma, psoriatic arthritis, osteoporosis,osteoarthritis, rheumatoid arthritis, neurological dysfunction or theirsymptoms, e.g., dementias such as Alzheimer's Disease, Parkinson'sDisease, or memory loss conditions, in osteoporosis or in cancer such asbreast cancer. The compounds can prevent NFκB from translocating fromthe cytoplasm into the nucleus and thus can increase the ratio ofcytoplasmic NFκB to nuclear NFκB. The F1Cs may inhibit activation ofNFκB-mediated transcription while NFκB is bound to target DNA sequencesin the nucleus. Alternatively, the F1Cs can activate or enhance theexpression of or one or more activity of a transcription factor such asT-bet in, e.g., a subject's cell(s) or tissue(s) or in enzyme orcell-based assays. In this aspect the compounds are used to treat,prevent or to ameliorate conditions or symptoms that are associated withdeficient expression or activity of T-bet in conditions such as immunedysfunction in an immunosuppression condition, aging, an infection, acancer or precancer as described herein or in the cited references.

The invention provides methods to identify compounds to regulate immuneor other biological responses in a context-sensitive manner. Suchcompounds modulate differential expression in a cell of the level of oran activity of, eg., 4, 5, 6, 7, 8 or more genes or gene products,comprising administering an effective amount of a F1C. The genes or geneproducts are USF1, c-Fos, EGR1, Cul1, RIPK2, IκBα, IκBKb, NF-κB, NF-κB2,NF-κB1 p50, Fn14 (fibroblast growth factor-inducible 14), TWEAK(TNF-like weak inducer of apoptosis), NEMO (NF-κB essential modifier),FCAR, c-Fos/C/EBPβ, RANTES, ICAM1, TSG (TNFAIP6), IL-2 receptor α, GRO2,GRO3, HO1, Jun B, c-Fos/JunB complex, JunB/ATF3 complex, c-Jun,c-Fos/c-Jun complex, ATF-3, MMP1, TSG-6 (TNFAIP3), AP-1, EGR1, TGFβ,ATF-3/c-Jun complex, c-Fos, MMP3, IL-8, STAT5A, STAT5B, CDKN1A, IFNγreceptor 2 (IFNγR2), T-bet, C reactive protein, immunoglobulin E, anAP-1 family protein, GATA-3, Jak2, Tyk2, stat1, stat3, stat4, stat5,MIP-1α, MIP-2, IP-10, MCP-1, TNF-α, TNF-β, LT-β, IFN-α, IFN-β, TGF-β1,NF-κB, IL-1α, IL-1β, IL-4, IL-6, IL-10, IL-12 receptor β1, IL-12p35,IL-12p40, IL-23, IL-23 receptor or another gene or gene productdisclosed herein, including in Table 1. The compounds identified by thescreening methods modulate the expression of dysregulated genes andrestore or enhance normal immune responses in conditions where unwanteddysregulation contributes to the establishment or progression apathological condition such as an infection, an autoimmune disorder, acardiovascular condition or a neurological condition.

Thus, in some embodiments, the level or a biological activity of 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more of COX-2, IL-1β, TNFα, TNFαreceptor 1, TNFα receptor 2, TNF receptor-associated factor, MIP-1α,MCP-1, IFNγ, IL-4, IL-4R, IL-6, IL-6R, IL-8, IL-8R, IL-10, IL-10R,IL-12, IL-12R, IL-18, IL-18R NFκB, IkBα, AP-1, GATA-3, 11β-HSD1, cPLA2,iPLA2, cortisol, ROS, PGE2, PGD2, leukotriene A4, leukotriene B4,leukotriene C4, iNOS or GM-CSF are optionally measured and they aregenerally detectably reduced, e.g., RNA or protein levels are reduced byabout 10-95% or about 20-95% or more compared to suitable untreatedcontrols. In these embodiments, the level or a biological activity of 4,5, 6 or more of IFNα, INFα receptor, IL-12, an IL-12 receptor, (e.g.,IL-12Rβ2), PPARα, PPARγ, and T-bet are optionally measured and they aregenerally detectably increased. In a chronic infection condition, e.g.,HIV in humans, autoimmunity, a chronic fungal or parasite infection orin a precancer or cancer condition, e.g., benign prostatic hyperplasia,the progression of the condition may be slowed over a period of 1, 2, 3,4, 5 or more years. In these embodiments, the subject's conditionbecomes more manageable with a reduced incidence or severity of sideeffects, e.g., a detectable halt, slowing, reversal or decreasedincidence of wasting, dementia, CD4 cell count decreases or viral loadincreases, which tend to occur over time in HIV infected humans or ahalt, slowing or reversal of pathogen or precancer or cancer cellreplication.

These effects are typically observed after administration of aneffective amount of a F1C using, e.g., a method or dose essentially asdisclosed herein. The simultaneous reduction of multiple biomoleculesprovides a method to modulate immune responses by modulating multiplepathways that lead to a common condition such as inflammation. Thisprovides a method to treat or ameliorate, e.g., acute or chronicinflammation, a cancer, an infection or a symptom associated therewith,or to slow the progression of or reduce the severity of these conditionsor their symptoms.

Previously described methods can be used to measure the amount, activityor cellular location of various biomolecules such as cytokines ortranscription factors. See, e.g., U.S. Pat. Nos. 6,107,034, 5,925,657,5,658,744, 4,016,043 and 3,850,752, S. Szabo et al., Cell 2000100:655-669, Y. Nakamura et al., J. Allergy Clin. Immunol. 1999 103(2pt. 1):215-222., R. V. Hoch et al., Int. J. Cancer 1999 84:122-128.These methods can be used to measure the effects of the F1Cs ontranscription factors or receptors in cells or tissues that have beenexposed to the compounds.

Without wishing to be bound to any theory, the F1Cs may modulatemultiple biomolecules in a microenvironment sensitive manner or context.The effects of the compounds can provide a decrease in a particularmolecule such as IFNγ and a decrease in inflammation associated withelevated IFNγ levels or activity without eliminating beneficial effectsof the molecule. This effect arises from decreasing the level oractivity of a biomolecule such as IFNγ in cells that are dysregulated,while allowing normal immune cells to produce sufficient amounts of thesame molecule to perform normal immune functions. In locations where thebiomolecule is needed for activity, e.g., in lymph nodes or spleencells, sufficient amounts of the modulated molecule are present toelicit a desired response, while the level of the molecule in cells incirculation decreases. The compounds can increase IL-13, IL-15, IL-17 orIL-18 in conditions where a subject has a deficient Th1 immune response,e.g., in infection or cancer. Conversely, the compounds can decreaseIL-13, IL-15 or IL-18 in conditions such as allergy or autoimmuneconditions, e.g., multiple sclerosis, where an excess Th1 immune statusmay prevail.

In general, the F1Cs will detectably decrease the synthesis or one ormore biological activity of one or more of these molecules (or othertranscription factors or receptors disclosed herein) when such synthesisor activities is associated with the establishment, maintenance,progression or enhanced severity of a clinical condition or symptomdisclosed herein. Conversely, the F1Cs will generally detectablyincrease the synthesis or one or more biological activities of one ormore of these molecules (or other transcription factors or receptorsdisclosed herein) when such synthesis or activity is associated with thetreatment, prevention, cure or amelioration of a clinical condition orsymptom disclosed herein.

These decreases or increases compared to suitable controls can berelatively small, including changes near the lower limits ofdelectability for such molecules using known or new assays, e.g., adecrease or increase in the synthesis or biological activity of at leastabout 2%, about 5%, about 10% or about 20%. Such changes can be modestor relatively large, e.g., at least about a 50% change, at least about a90% change, or at least about a 200% change, up to about a 5-fold, abouta 10-fold, about a 100-fold or greater decrease or increase in thesynthesis or biological activity of the affected molecule(s) compared tosuitable controls. These changes are typically measured relative tocontrols that lack a F1C or that use known agonists or antagonists ofone or more relevant molecules. Assays can be based on measuringdecreases or increases in, e.g., one or more of protein levels, RNA ormRNA levels, a ligand binding activity, transcription of a targetgene(s) and the like. Suitable assay protocols include any suitablepolymerase chain reaction assay to measure an RNA or mRNA, any suitableblotting protocol for nucleic acid or for protein such as a Northern orWestern blot method or any transcription assay, including DNAfootprinting or a gene expression or gene function assay. Typically theF1Cs will effect detectable changes in the synthesis or one or morebiological activities in a concentration range of about 0.5×10⁻⁹ M toabout 3×10⁻⁵ M. Exemplary compositions that comprise a F1C for use in,e.g., in vivo animal assays, in vitro cell or tissue culture assays orin cell free assays, will comprise one or more suitable solvents orvehicles including DMSO, ethanol, water and a suitable tissue culturemedium.

One or more of these transcription factors, receptors or complexes canbe a component in methods when, e.g., they are used with a F1C incell-free assays or in tissue culture assays. Formation of thesecomplexes in cells or analysis of the effects of F1Cs on one or more oftheir biological activities is facilitated by inserting into the cells aDNA construct(s) that expresses one or more of these proteins, e.g.,mammalian or yeast cells containing a stable DNA construct or aconstruct used for transient transfection assays. Methods to performassays or to induce biological responses in vitro or in vivo using theF1Cs as agonists, antagonists or as reference standards are essentiallyas described, see, e.g., U.S. Pat. Nos. 5,080,139, 5,696,133, 5,932,431,5,932,555, 5,935,968, 5,945,279, 5,945,404, 5,945,410, 5,945,412,5,945,448, 5,952,319, 5,952,371, 5,955,632, 5,958,710, 5,958,892 and5,962,443; International Publication Numbers WO 96/19458, WO 99/41257and WO 99/45930. The complexes or assay systems, that comprise a F1C andone or more of these molecules are embodiments of the invention, as arethe use of these compositions when employed in the practice of any ofthe assay methods or in any of the clinical treatment methods disclosedherein or in the cited references.

Invention embodiments include a method comprising contacting a F1C(s)with a cell(s), whereby the F1C(s) forms a complex with a steroidhormone receptor or results directly or indirectly in the modulation ofa biological activity of the steroid hormone receptor or a gene that itregulates. The steroid hormone receptor may be an orphan nuclear hormonereceptor or a characterized receptor such as the glucocorticoidreceptor, estrogen receptor or the androgen receptor that displays amoderate or high binding affinity for the F1C(s). In some embodiments,the nuclear hormone receptor is a known receptor. Biological effectsfrom interaction of a F1C and a receptor can lead to interference withthe replication or development of a pathogen or the cell(s) itself,e.g., detectably inhibited proliferation of cancer cells. For example,expression of HIV transcripts in HIV-infected cells may be altered. Thereceptor-F1C complex may directly interfere with LTR-dependenttranscription of HIV genes, leading to reduced viral replication.Alternatively, such effects can include the decreased synthesis orbiological activity of a protein or gene product that is associated withthe establishment, maintenance or progression of a disease conditiondescribed herein or in the cited references.

An aspect of F1C biological activity is their capacity to modulate thecapacity of cells or tissues described herein to express one or moreenzymes that mediate phase II detoxification and reduction of damagingor reactive species such as xenobiotics, including electrophiles andchemical carcinogens, and superoxide radicals or hydrogen peroxide.Modulation of these genes is mediated by one or more transcriptionfactors or complexes of factors that include bZip transcription factorssuch as Nrf2 (NF-E2 related factor 2, Unigene symbol Nfe2L2) and Mafproteins such as MafG, MafK or MafF. These factors bind to cis-elementssuch as EpRE (electrophile response element) or ARE (antioxidentresponse element). EpRE and/or ARE elements present in the promoters ofphase II detoxification enzymes including NAD(P)H:quinineoxidoreductase-1 (NQO1) and glutathione-S-transferase (GST) as well ascellular defensive enzymes such as thioredoxins, heme oxygenase 1 (HO 1,or HMOX1), the catalytic and regulatory subunit γ-glutamylcycleinesyhthetase (γGCS or GCLM) and xCT (SLC7A11), a subunit of thecystine/glutamate exchange transporter. EpRE and ARE mediateupregulation of these genes following exposure of the cells to manyxenobiotics. In situations where enhanced expression of these genes ortranscription factors is desirable, the F1C upregulate the activity orlevels of one or more of these factors and/or enzymes.

Thus, in some embodiments the F1C are used to modulate the level oractivity of one or more of Nrf2, a thioredoxin, NQO1, GST, HO 1, thecatalytic subunit of γGCS, the regulatory subunit of γGCS and xCT incells or tissues that are exposed to a F1C. In some embodiments, thecells or tissues are treated with a F1C when an unwanted acute orchronic condition such as toxin exposure or elevated oxidative stress ispresent in the cells or tissues. Such conditions can occur, e.g., asdescribed elsewhere herein, including in acute or chronic pathologicalinflammation conditions, acute or chronic infections and traumaconditions. The effect of the F1Cs is restoration of normal expressionor establishment of desired levels of expression of one or more of thesetranscription factors or enzymes, e.g., decreased expression insituations where chronic over-expression occurs. Thus, the F1C can beused to modulate these or other genes described herein, e.g., todecrease expression or mRNA levels or protein levels of one or more ofthese or other genes in clinical conditions where excess or unwantedexpression or levels of the gene is associated with establishment,maintenance, severity or progression of the clinical condition resultingin clinical improvement in the disease or an unwanted symptom.

Other genes in cells or tissues in vitro or in vivo that the F1Cs canmodulate include 1, 2, 3, 4, 5, 6 or more of the following genes (whichare listed by their Unigene symbols): LOC55967, 37149, LOC64148,LOC57823, AGPAT1, PHACS, OAS1, OAS3, OASL, IFRG28, C(27) 3BETA-HSD,LOC55831, HMGCR, HMGCS1, PDPK1, HPD, AIRP, PFKFB3, DHCR7, OGG1, ADAM9,ADAMTS1, ADAMTS10, AKAP1, AKAP10, AKAP3, AKAP4, AKAP8, TOB3, ABO, AIM1,LOC55902, ACAT2, ASMTL, ACP5, OA48-18, ACO1, ACO1, ACR, ABLIM, ACF7,LOC81569, ARPC4, ACTC, ACTG2, ACTL6, ALCAM, PC4, ATF1, ATF3, ATF4,AICDA, ABR, ACVR1, ACVR2, ACADS, ACOX1, ACOX2, AOAH, ACYP1, AD-003,LOC55829, AP1B1, AP1G2, AP1S1, AP2M1, AP3B2, AP3M1, ADD3, ADORA2A,ADORA2B, ADA, ADAR, ADAT1, AMPD1, ADCY3, ADCY7, AK1, ADSL, ARF4, ARF4L,ARF6, ARL4, ADPRTL2, ART3, LOC51578, ADRB2, ADRB3, ADM, ADMR, AGER,AFG3L1, AFG3L2, AGC1, AGRP, ALDH1A1, ALDH1B1, ALDH2, AKR1C1, AKR1C2,AKR1C3, AKR7A2, AKR7A3, ALDOC, ALG5, ALPI, ALPL, ABH, AF1Q, AIF1,KIAA1017, ATRX, A2M, A2M, AMACR, ASPSCR1, ABP1, ACCN1, ACCN2, AOC2,ACY1, ALAD, ALAS1, LOC64167, AMPH, AGL, APPBP1, ALS2CR2, AGTRL1, ANK2,ASB1, ASB2, ANXA1, ANXA11, ANXA9, MOX2, KIN, AMHR2, KIAA0106, APELIN,APG5L, API5L1, APXL, APOARGC, APOC4, LOC51275, APAF1, APAF1, APEXL2,AQP1, AQP2, LOC51326, HSU52521, ARG2, AVPR1B, ARMET, ASS, ALX3, ALX4,ACTR3, ARTN, ARNTL, AIP, ARSA, ARSB, ARSD, ASH2L, AMSH, AKNA, ACLY,ATP5F1, ATP51, ATP5J, ATP5A1, ATP5C1, ATP50, ATP2A1, ATP2B1, ATP2B2,ATP2C1, ATP7B, ATP6D, ABCA3, ABCA4, ABCA5, ABCA7, ABCC5, ABCD1, ABCE1,ABCF1, ABCF2, ABCG4, AUH, BAL, B29, B7-H3, BPI, BIRC1, BIRC3, BIRC4,BIRC7, BIRC8, BAF53A, BAIAP2, BARX2, BHLHB2, BLZF1, BATF, BTEB1, BCL11A,BCL2, BCL3, BCL6, BCL7A, BCL9, BTG1, BBC3, BMF, BMF, BNIP3, BAG2, BIK,BCL2L1, BCL2L11, BOKL, SBBI42, BFSP1, BBP, ICAT, GAL3ST-4, BACE, BACE2,BACE2, BTRC, BF, BID, BIC, BLVRA, BTD, BPHL, BM88, BN51T, BPOZ, BRI3,BAI2, BSMAP, BCAT2, BCKDHB, BCRP2, BCAR3, BIG1, BIG2, BAZ1A, BAZ2A,BAZ2B, BP75, BRD1, BRD2, BRD3, BRUNOL5, BRUNOL6, BTK, BTBD2, BTG2, BUB3,BUP, BRF2, BBOX1, BTN3A1, BYSL, LOC81558, C2F, ZFP26, C6.1A, C9orf10,CABP1, CHP, CACNB1, CALM2, CAPN1, CAPN2, CAPN5, LOC57118, H_GS165L15.1,CHST2, CA3, CA11, CA12, CPM, CLC, CROT, CBL, CSNK2A2, CSN2, CFLAR,CASP10, CASP2, CASP6, CASP8, CARD14, CECR5, CECR6, CAT56, CTSC, CTSE,CTSL, CTSS, CTSW, CTSZ, LOC56996, CITED1, CEBPE, CBF2, CNOT2, CD14,CD1A, CD1D, CD2AP, CD33, CD36L1, CD3D, ASE-1, CD3G, CD4, CD44, CD5L,CD69, CD72, CD79A, CD8A, CD8B1, CD83, CD84, CDCl₄A, CKS2, CEP2, CDC45L,CLK2, TOK-1, CDV-1, CDC25A, CDC25C, CGR19, GP110, CREG, CRABP1, CENTA1,CENTB2, CENTG1, CETN3, CENPA, CENPB, CENPF, CEP1, CER1, CCM1, LOC51148,CLN2, CLN3, FIGF, LOC50999, CGI-152, CGI-152, CHES1, CCR1, CCR8, CCRL2,CX3CR1, CMKLR1, CHN1, CLCN2, CLCN3, CLCA1, CLCA4, CLIC1, CHK, CHKL,LOC56994, CHRNA3, CHRNA4, C4S-2, C4ST, CSPG4, CSPG6, CHAC, CGB8, CSH1,CHAF1B, CBX4, CHD1L, CHD3, CHD3, C11orf14, C21orf11, C22orf5, CTRL,CIG30, CIZ1, LUC7A, CS, CLTCL1, CLDN12, CLDN15, CLDN17, CPSF3, CPSF5,CPSF6, CLU, MERTK, LOC55907, VI, IRLB, JPO1, CIA, CLP, F3, F9, F8, F8A,LOC51137, COPA, CKN1, COQ7, CRSP6, CRSP7, CIAS1, CLPS, COL2A1, COL4A3BP,COL5A3, COL7A1, COL19A1, COL15A1, COL16A1, COL18A1, MIC1, CSF1R, CSF3,Cl QA, C1R, C2, C5R1, C8A, C8G, CPLX2, GJA10, CGTHBA, CHUK, CNTN5,CNTNAP1, COPS4, CPNE3, CBFB, CBFA2T3, CORO2A, COX10, CPXCR1, CRY1,CRYGA, CRYZL1, CSK, CTDP1, CLECSF6, CLECSF9, LOC51266, CUGBP2, CUL1,CUL2, CUL3, CUL4B, CUL5, HUMMHCWLA, CNGB1, CCNB3, DMTF1, CCNE2, CCNG2,CNNM2, CNNM4, CDK10, CDK3, CDK7, CDKNLA, CDKNLB, CDKN2B, CDKN2C, CDKN2D,CDKN3, CTH, CBS, CST8, CSTA, CST3, CSRP1, CSRP3, CHORDC1, CCBL1, CRIP2,CHIC2, CYSLT1, CARS, CTNS, CMAH, CYB5, HCS, COX5A, COX7C, LOC57404,CYP51, CYP1A1, CYP1B1, CYP2A6, CYP2D6, CYP2E, CYP2J2, CYP4F3, CYPL1B1,CYP21A2, CYP24, CYP27B1, CRLF2, CREME9, CNK, N-PAC, KIAA0068, PIR121,#22, LOC81501, DRIL2, DDXBP1, DDX10, DDX16, DDX19, DDX8, DELGEF, DAF,DEFB2, DSS1, DLL1, DLL3, DSIPI, KIAA1365, DRPLA, DNASE1, DTYMK, #23,D4ST-1, #24, DDEF1, DRG2, DGKZ, DGAT, DIAPH1, DEF6, DGS-D, DGS-H, DHODH,DPYSL2, DPYD, HUM2DD, DDAH1, DDAH2, HSA249128, DTR, DLG4, DISC1, SAS10,DLX2, UBD, DKFZP434A236, DKFZP434B103, DKFZP434B168, DKFZP434C212,DKFZP434I216, DKFZP434N014, DKFZP434N043, DKFZP434N161, DKFZP564C1940,DKFZP564M1416, DKFZP5640123, DKFZP566C134, DKFZP566F0546, DKFZP566F2124,DKFZP566K023, DC8, CTRP5, DKFZP586M1523, DKFZP727C091, DNMT1, DNMT2,DNMT3B, DFFB, DNAJA1, DNAJB11, DNAJB4, DNAJB5, DNAJB6, DNAJB6, DNAJB9,DNAJC3, DOK2, DPM1, DO, DRD1, DRD5, DUX4, DORFIN, ADAR3, DSCR4, DONSON,DUOX1, DUSP1, DUSP11, DUSP12, DUSP2, DUSP3, DUSP4, DUSP5, DUSP7, DYRK3,DYRK4, DNCI1, DKC1, DMWD, EP300, E2F5, SMURF1, ELF1, EAF1, EAP30, EBF,EDR1, EGR1, EGR2, EGR4, EVI2A, EVI2B, ENC1, ENTPD1, ENTPD2, EMR1, EMR3,EGLN1, EHD1, EHD2, ETFB, HSA277841, ELK4, EMK1, ELKS, ELL, EVC, ELL2,ELOVL4, EMD, KIAA0709, ENG, PODLX2, ERO1-L(BETA), ENDOFIN, EDG4, EPAS1,EZFIT, EDN1, ET(B)R-LP-2, EN1, HEF1, ERH, EZH1, ENO3, ENO1B, EFNA2,EFNB1, LOC84648, EPS15R, EPM2A, EPIM, EMP2, EPLIN, DD96, EPHX1, EBI3,ERGL, EPB41L2, EPB72, LOC51145, EPOR, ECRG4, EBAG9, EBBP, ETV1, ETV5,EEF1B2, EIF1AY, EIF2S3, EIF3S10, EIF3S7, EIF4G3, EIF4B, EIF4EL3, EIF5,EIF5A, EIF5A2, ETF1, EXTL1, EXTL2, LAK-4P, KIAA0165, EMILIN-2, XLKD1,ECM2, EYA2, FGD1, FHR5, FANCE, FANCF, FNTA, FNTB, FADD, FABP5, FADS3,FAAH, FACL2, FACL3, FACL5, FOSB, FBXL11, FBXL3A, FBXL4, FBXL9, FBXW2,FBXW3, FBXO11, FBXO2, FBXO22, FBXO24, FBXO3, FBXO7, FBXO8, FBX30, FCAR,FCGBP, FCGR2B, FCGR3A, FE65L2, FES, FER, FTHL17, FTL, FALZ, HSRNAFEV,#25, FOP, FHOS, FBN1, FGL1, FGF11, FGF9, FGFR1, FGFRL1, FLRT1, FBLN1,FLNB, FLNC, M83, FRAP1, LOC51303, LOC51661, FKSG42, FKSG58, FKSG64,FKSG87, FMO1, FMO3, FMO5, LOC51167, FLJ00005, LOC51066, FLT3LG, FLT4,FOLR2, FSTL1, FSTL3, FOXC2, FOXF1, FOXG1A, FOXO1A, FOXO3A, FPRL1, FS,FOSL2, FOSL1, FHL1, FHL2, FHIT, FRDA, FPGT, FUCA1, FUT5, FUT8, FUSIP2,FXYD1, FYN, FYB, FZR1, ZSIG37, #26, RDC1, GPR19, GPR31, GPR34, GPR35,GPR41, GPR50, GPR61, GPR64, GPR65, GPR68, GPR7, GPR84, GPR91, GPRC5C,GPRC5D, GSPT2, GTSE1, LOC51161, G5C, G6C, GABARAPL1, GABARAPL2, GAJ,GLA, GALR2, LOC85329, HSY11339, GGCX, GGH, GDAP1, GJA3, GJA8, GJB2, FGR,GRPR, GATA2, GATA6, GCN1L1, GCN2, GMDS, LOC51291, #27, HSA250839, #28,RES4-25, GOA, GTF2A1, GTF2B, GTF2F1, GTF2F2, GTF3C1, GPHN, GGPS1,LOC51087, LOC64396, LOC51738, #29, GK003, GL002, GMFB, GBAS, GLTSCR1,GLP1R, GMEB2, #30, GPI, GLUT11, G6PC, G6PD, GAD1, GLUD1, GLUD2, GRIP1,GRIA2, GRIN1, GRIN2A, GRIN2C, GRM4, GRM6, GCLM, GLS, GLRX, GCDH, GPX2,GPX3, GSTA2, GSTA4, GSTM1, GSTM2, GSTM5, GSTP1, GSTT1, GSTT2, GSS,GAPDS, GNPAT, GATM, GCAT, GNMT, GYS1, GYG2, GYPA, GYPE, GP3ST, GP1BB,GP9, GARS, GLO1, GPC1, GLG1, GOLGA1, GOLGA2, GOLGA4, GOLGB1, GOLPH2,GOLPH4, GOSR1, GOLTC1, KIAA0855, GLP, GNRH1, GNRHR, GNLY, GZMB, GAB2,GRO1, GRO2, GRO3, PLA2G13, GADD45B, GRB10, GFER, LOC84649, HUMGT198A,GTF21RD1, GCH1, GRAF, GEM, RAGB, GTT1, GNAL, GNAI1, GNAZ, GNB5, GNAQ,GNG10, KIAA0277, GUCY1B2, GUCA1A, GUCA2B, #31, #32, H₁F₂, H₁F₄, HLX1,H₂BFQ, H₂BFR, H₃FD, H₃FK, H₃FM, H₃F₃B, H326, H₄FH, H₄FM, HRY, HP,LOC51773, #33, HCR, #34, #35, HSP105B, HSPE1, HSPB7, HSPA1A, HSPA1B,HSPA6, HSPA1L, HSPCB, APG-1, HIP, KIAA0054, HELLS, KIAA0928, HEM1, HHEX,HMOX1, HMOX2, HEBP, HBE1, HPX, HCK, HS3ST3B1, HS6ST, HSPG2, HPSE, XIP,LOC63928, LOC51339, HPS, HHLA2, HNRPA0, HNRPA2B1, HNRPF, HNRPM, HNRPU,HDLBP, HGRG8, HMG14, HMG2, HMGIY, HIRIP3, HIRIP5, HRH1, HRH2, HBOA, #36,HDAC7A, HRB, HTATIP, BAT8, TCF-3, HNK-1ST, HESX1, HOXA1, HOXA11, HOXA6,HOXA7, HOXB5, HOXC10, #37, HERPUD1, RRS1, HOOK2, HOOK3, HCF-2, HP1-BP74,LOC51202, HRASLS, HSKM-B, HSPBP1, HSPC018, HSPCO22, HSPCO25, HSPCO30,LOC51669, HSPCO39, LOC51125, LOC51122, HSPCO49, HSPCO55, HSPCO63,HSPC071, HSPC073, HSPC125, HSPC142, HSPC144, HSPC154, HSPC156, HT014,HTGN29, LOC58514, #38, HYPK, HMMR, HYAL3, HSD11B2, CG018, FLJ00060,LOC54557, LOC51235, HSPC228, HSPC192, #39, LOC56270, AF140225,BK1048E9.5, 13CDNA73, DJ1057B20.2, DJ1181N3.1, DJ465N24.2.1, DJ796117.1,FELL, DKFZP434F0272, DKFZp434G0522, DKFZP434K046, DKFZP434N1429,DKFZP434N185, DKFZp434P1115, DKFZP566G1424, DKFZP761L0424, DKFZp762B226,KIAA1630, DKFZp7620076, FLJ00001, FLJ10074, FLJ10081, FLJ10201,FLJ10357, FLJ10407, FLJ10420, FLJ10512, FLJ10656, FLJ10697, FLJ10707,FLJ10719, FLJ10826, FLJ10830, FLJ11113, FLJ11183, FLJ11560, FLJ12221,FLJ12572, FLJ12895, FLJ20033, FLJ20097, FLJ20203, FLJ20281, FLJ20297,FLJ20333, FLJ20689, FLJ20793, FLJ20886, FLJ20986, FLJ21877, FLJ22035,FLJ22263, FLJ22341, FLJ22376, FLJ22593, FLJ22955, FLJ23059, FLJ23119,FLJ23132, FLJ23316, FLJ23563, MGC10485, MGC14961, MGC20255, MGC20496,MGC4856, MGC5618, PRO1546, LOC63923, HIF1A, HIG2, IDN3, IDS, LNIR, IK,IKKE, ILVBL, IER3, HIVEP2, IGHM, ISLR, IGSF2, IPW, INHBA, INHBC, IBTK,ID1, ING1, ING3, IKBKB, IKBKAP, ITPR1, ITPR2, ITPKA, ITPKB, INPP4B,INPP5B, INSIG1, LOC55971, IGF1R, IGF2AS, IGFBP6, IGFBP4, INSM1, ITM1,ITGA1, ITGA2B, ITGA3, ITGA5, ITGA6, ITGB3, ITGB4, ITGB7, ITGB7, ICAM1,ICAM2, ICAM5, ICSBP1, IFNGR1, IFNGR2, IRF1, IRF2, IRF4, ISG20, IFNA17,IFNA6, IF127, IF130, IF141, IF141, IFRD1, IL1RN, IL1RL2, IL1A, IL1B,FIL1(EPSILON), FILL, IL10, IL10RA, IL11RA, IL13RA1, IL15RA, IL17E,IL18BP, IL18R1, IL18RAP, IL2RA, IL2RB, #40, IL23A, IL6, IL7R, IL8,IL8RA, IL1HY2, #41, SYNCOILIN, ITSN1, 1HABP4, INVS, IRX5, IDI1, ICMT,IVD, JDP1, JAG1, JAG2, SSI-1, JAK1, JM4, JUNB, JUND, KLK4, KLK6, KLK8,KLKB1, KAI1, KPNB2, KPNA3, KATNA1, KATNB1, #42, AB026190, KEL, KRT3,KRT6A, KAP4.10, KAP4.2, KRTHB1, KRTHB6, KIAA1274, KIAA0007, KIAA0008,KIAA0009, KIAA0014, KIAA0020, KIAA0036, KIAA0074, KIAA0100, KIAA0101,KIAA0133, KIAA0135, KIAA0140, KIAA0143, KIAA0146, KIAA0166, KIAA0172,KIAA0185, KIAA0189, KIAA0191, KIAA0194, KIAA0196, KIAA0202, KIAA0211,KIAA0225, KIAA0229, KIAA0232, KIAA0240, KIAA0244, stab1, KIAA0247,KIAA0251, KIAA0256, KIAA0265, KIAA0268, KIAA0290, KIAA0295, KIAA0306,KIAA0321, KIAA0323, KIAA0328, KIAA0332, KIAA0335, KIAA0342, KIAA0346,KIAA0356, KIAA0365, KIAA0368, KIAA0370, KIAA0404, KIAA0408, KIAA0410,KIAA0417, KIAA0418, KIAA0419, KIAA0429, KIAA0430, KIAA0433, KIAA0467,KIAA0469, KIAA0470, KIAA0535, KIAA0552, KIAA0561, LOC114659, KIAA0586,KIAA0590, KIAA0595, KIAA0605, KIAA0615, KIAA0618, KIAA0635, KIAA0637,KIAA0645, KIAA0649, KIAA0663, KIAA0671, KIAA0680, KIAA0685, KIAA0710,KIAA0711, KIAA0713, KIAA0716, KIAA0726, KIAA0728, KIAA0737, KIAA0752,KIAA0769, KIAA0773, KIAA0775, KIAA0792, MAST205, KIAA0843, KIAA0860,KIAA0871, KIAA0872, KIAA0874, KIAA0893, KIAA0907, KIAA0913, KIAA0914,KIAA0922, KIAA0924, KIAA0939, KIAA0945, KIAA0957, KIAA0963, KIAA0964,KIAA0971, KIAA0982, KIAA0990, KIAA1001, KIAA1008, KIAA1009, KIAA1018,KIAA1023, KIAA1041, KIAA1042, KIAA1043, KIAA1049, RAP140, KIAA1116,KIAA1128, KIAA1143, KIAA1150, KIAA1171, KIAA1199, KIAA1203, KIAA1204,KIAA1224, KIAA1228, KIAA1234, KIAA1235, KIAA1237, KIAA1240, KIAA1243,KIAA1244, KIAA1246, KIAA1253, KIAA1255, KIAA1266, KIAA1271, KIAA1278,KIAA1288, KIAA1292, KIAA1295, KIAA1298, KIAA1301, KIAA1303, KIAA1305,KIAA1306, KIAA1311, KIAA1320, KIAA1332, KIAA1337, KIAA1339, KIAA1340,KIAA1345, KIAA1350, KIAA1363, KIAA1376, KIAA1387, KIAA1388, KIAA1402,KIAA1409, KIAA1414, KIAA1424, KIAA1430, KIAA1441, KIAA1451, KIAA1457,KIAA1460, KIAA1464, KIAA1467, KIAA1483, KIAA1484, KIAA1485, KIAA1486,KIAA1509, KIAA1512, KIAA1513, KIAA1522, KIAA1524, KIAA1527, KIAA1528,KIAA1535, KIAA1538, KIAA1542, KIAA1547, KIAA1549, KIAA1553, KIAA1554,KIAA1557, KIAA1559, KIAA1563, KIAA1571, KIAA1587, KIAA1598, KIAA1599,KIAA1617, KIAA1638, KIAA1641, KIAA1656, KIAA1666, KIAA1668, KIAA1673,KIAA1677, FLJ10898, KIAA1694, KIAA1698, KIAA1701, KIAA1705, KIAA1708,KIAA1710, KIAA1725, KIAA1726, KIAA1727, KIAA1728, KIAA1737, KIAA1741,KIAA1742, KIAA1758, KIAA1762, KIAA1771, KIAA1785, KIAA1789, KIAA1795,KIAA1798, KIAA1802, KIAA1811, KIAA1813, KIAA1814, KIAA1819, KIAA1821,KIAA1832, KIAA1842, KIAA1858, KIAA1862, KIAA1870, KIAA1887, KIAA1896,KIAA1899, KIAA1908, KIAA1917, KIAA1919, KIAA1937, KIAA1938, KIR3DL1,KIR3DL2, KIR3DS1, KIR2DL4, KIR2DS5, KLRF1, KIF13A, KIF13B, KIF1C, KIF3A,KIF5B, KIFC3, KIF1B, KNSL5, CENPH, KITLG, KR18, SZF1, SERHL, KRML,LOC51045, KLF1, KLF4, ZK1, KUB3, KCNIP2, KYNU, KMO, HADHSC, LDHL, LMNA,LMNB1, LMNB2, LAMA2, LAMA5, LTBP1, LTBP3, LTBP4, LBP-9, LCHN, LOC51157,LGALS3, LGALS3BP, LGALS9, KIAA0821, HSOBRGRP, LRRFIP2, LZTFL1, LETM1,LRPPRC, LRRC3, RNO2, LZTR1, LIF, LILRA3, ILT10, LILRB2, LILRB4, IRC1,LENG1, LENG3, LAIR2, LIG3, LIG4, KIAA0175, FLJ23293, KIAA0203, SLY, SV2,E2-230K, DKFZP564M112, ARV1, LASP1, LDB2, LIMK2, LMO2, LMO4, LMO6, LHX2,LIM, LIN-7-C, LIN-7B, LIPA, LPIN2, LHFP, LHFPL2, LSR7, NUDE1, LIV-1,LOC88523, LDLR, #43, LDLB, LDLC, LRP3, QP-C, #44, LSM1, LUC7L, LFNG,LABH1, T1A-2, LW-1, LOC51088, LNK, LY117, LY64, LCP2, LBC, LRMP, LTB,LPAAT-delta, LYSAL1, LALP1, LAPTM5, LOXL3, LOC51300, HML2, MACMARCKS,MARCO, MST1, MADH4, MADH7, MAD2L1, MADP-1, MEF2A, MAGEF1, FLJ20798,MAGOH, LOC51678, HLA-DRB5, MVP, KIAA0936, MPI, MPDU1, MAN2A2, MGAT1,MGAT3, MKP-7, MPN, MRG, MAML1, MMP1, MMP10, MMP11, MMP14, MMP15, MMP19,MMP2, MMP3, MMP7, MMP8, MNT, MAD, MAX, MBLR, MEFV, MRE11A, MEIS2, MEIS1,MC1R, MAGEA6, MAGED1, MAGEE1, MDA5, MS4A1, MS4A4A, MS4A6A, MS4A7,LOC51336, LOC51337, MSLN, CPX-1, MTF1, MSRA, MBD4, MTHFD2, MGST1, MAP4,MAPT, MAPRE2, MAPRE3, MIP-T3, MID2, LOC55972, LOC56993, MRP63, MRP64,MRPL1, MRPL12, MRPL13, MRPL15, MRPL16, MRPL17, MRPL32, MRPS24, MRPS25,MRPS33, MRPS36, TOP1 MT, MTRF1, MAPK1, MAPK7, MAPK8, MAP2K4, MAP3K1,MAP3K13, MAP3K14, MAP3K2, MAP3K5, MAP3K6, MAP3K8, MAP3K9, MAP4K1,MAP4K2, MKP-L, MLN51, MRF-1, MAIL, MAOA, MAOB, MMD, MRG15, MDM4,MPHOSPH9, #45, FLJ00029, #46, #47, #48, #49, #50, #51, #52, #53, #54,#55, #56, #57, #58, #59, #60, #61, #62, #63, MSTP031, MSTP043, MUC6,MCOLN1, MALT1, MADCAM1, MUL, MEN1, MINPP1, BMI1, MLH1, MAG, MPZL1, MNDA,MLL, MLLT1, MLLT6, MLLT7, MYOC, MB, MYO1E, MYO9B, MIR, MYO10, MYL5,MYL6, MLCB, MYBPC3, MYBPH, MTMR1, MYOZ, MACS, MX1, NAGA, HSA242910,NAT2, NDUFA4, NDUFA5, NDUFA7, NDUFA9, NDUFB1, NDUFB2, NDUFB3, NDUFB4,NDUFB6, NDUFS6, NDUFV3, NOX1, JFC1, #64, NPPA, CD244, BY55, NAP4, NDRG4,WWP2, LOC51667, NAF1, NEO1, NESCA, NESH, NAPG, LOC51162, LOC84687,NEDD4, NXPH2, NBL1, NAG, NEUD4, NF1, NEUROD1, NEUROD2, NEUROD4, NEUROD6,NGB, NRGN, NLGN2, NMU, NPAS1, NPAS2, NRP2, NTRK3, NSMAF, NCF2, NNT,NPC2, NBS1, NEK2, NEK3, NIN, NINJ1, NIT2, KIR-023 GB, NME7, NMNAT,NDRG3, NMT2, NOD2, NIMP, #65, NOT56L, NOTCH₃, HSNOV1, DJ434014.5, NSP1,NSP3, SGSH, NTHL1, NTT5, GS2NA, SP140, NFE2, NFE2L2, NFAT5, NFATC3,NFKB1, NFKB2, NFKBIA, NFKBIE, NFKBIL1, P84, MDM1, NRBF-2, NCOA1, NCOA4,AIB3, NR1D1, NR1D2, NR1H3, NR2C1, NR2F6, NR3C1, NR4A1, NR4A2, NR5A2,NRF1, NXF2, NXF3, NFYA, NFYB, NFX1, SC65, NOL3, NOLA2, NOLA3, NPM1,NSBP1, NUMBL, NRM, NYD-SP12, LOC51133, OA1, OR11A1, OR12D3, OR2C1,OR7E24P, OGT, OSM, OIP5, OPRL1, OPRM1, OPN1LW, OPN1SW, ORC2L, OAZ2,OAZIN, ORNT2, ORM1, OSRF, OSF-2, OSTF1, OCIA, OXR1, RODH, OLR1, OSBP,OSBPL2, FLJ10217, BITE, PAK6, PCAF, PIGPC1, p53DINP1, p53R2, P53AIP1,PAI-RBP1, PACE, PAX1, PAX4, PILR(BETA), PMX1, PRX2, PITX1, KIAA0992,PANX1, PAPA-1, PRCC, LOC55893, PARD6A, HUMPPA, PON2, PTMS, POR1, PVALB,PAXIP1L, PCQAP, PC3-96, PSIP1, PSIP2, PAF65A, PAF65B, PCTK3, PDLIM1,PDZK1, PDZ-GEF1, LOC51735, TOPK, PTX3, PMPCB, PYY2, PDI2, PAM, PPIL2,PPIF, PRF1, PCM1, PLIN, PRAX-1, PEX11A, PEX16, PXMP3, PEX1, PPARA,PPARG, PPARGC1, PET112L, PHF1, PMAIP1, MDS019, PCYT2, PPAP2A, PIK4CA,PICALM, PIGB, PIGC, PIGF, PIGH, PIP5K1B, PIP5K2B, PDE1B, PDE1C, PDE2A,PDE4B, PDE4D, PDE5A, PDE6A, PDE6C, PDE8A, PDE8B, PGAM1, PGAM2, PIK3CG,PIK3C2A, PIK3C2B, PIK3R1, P101-PI3K, PEPP3, PLA2G6, PLCE, PLCG1, PLD1,PLD2, PLSCR1, PLSCR3, LHPP, C8FW, #66, PSPH, PIM1, PIM2, PINX1,LOC96626, PIR, PTTG3, PL6, PGCP, PLAT, PLAU, PLGL, PLS1, PAFAH2, PDGFA,PDGFB, PDGFRA, PLEK, PSD, PLEKHA1, PSCD2, PSCDBP, PHLDA1, PHLDA3, PLEC1,PLAGL1, PLAGL2, PLXNB2, PLXNB3, PLXNC1, #67, #68, #69, #70, PVRL2,PAPOLA, PABPC1, PKD2L1, PQBP1, POLI, POLK, POLA, POLD3, POLL, POLM,POLQ, POLS, POLR2D, POLR2E, POLR2K, RPC39, POLR3K, #71, PMSCL2, POP4,POP2, POP3, MG61, PMS2, PMS2L3, CRIPT, HERG-3, KCNK15, KCNK3, KCNK5,KCNK9, KCNN2, KCNN3, KCNJ1, KCNJ11, KCNJ15, KCNJ16, KCNJ5, KCNJ6, KCNK4,KCNMB3, KCNMB1, KCNS1, KCNQ1, KCNQ2, KCNQ3, KCNA10, KCNA3, KCNA5, KCND1,KCNH3, POU2F1, POU6F1, #72, PRDM13, PRDM2, PRDM8, SET07, PBEF, PRAME,PFDN2, OKL38, PRP17, PSEN1, PRIM1, PRO0233, PRO0365, PRO0641, PRO0644,PRO1073, #73, PRO1900, PRO2000, #74, #75, PCOLCE2, PLOD, PGRMC1, PDCD4,PDCD5, PDCD6, PDCD61P, PDCD7, PIP, B4-2, PML, PPBP, PCSK7, PTGDR,PTGER2, PTGER4, PTGES, PTGIR, PTGIS, PART1, PSK, #76, LOC85414, PRM1,PRM2, PRSS11, PRSS16, SPUVE, PSMD4, PSMD9, PSMA3, PSMA5, PSMA6, PSMB10,AWP1, PCCX2, PDI, PIAS3, PKIG, PACSIN2, PRKCABP, PRKCG, PRKCQ, PRKCZ,PRKCL2, PKD2, NJMU-R1, NYD-SP15, PRKAA1, PRKACA, PRKAR2B, PRKWNK1, P3,LOC51207, PPP1CB, PPP1R12A, PPP1R14C, PPP1R15A, PPP1R2, PPP1R3B, PPM1G,PPP2R3, PPP2R5B, PR48, PPP3CA, PPP3CC, PPP4R1, PME-1, PPEF1, HSU79274,LOC84518, PRO51, PTK9, PTPN11, PTPN12, PTPN3, PPFIA1, PTPRG, PTPRO,PTPLA, LOC51184, PRKRIR, PCMT1, POMT1, AD013, PRG1, PRG2, LOC51685,U5-100K, PTDO11, PPFIBP2, #77, P2RX2, P2RX7, PURA, HM74, M96, #78, GPR,GPCR150, #79, SH120, PHTF1, KIAA0436, M6A, MRS3/4, N6AMT1, HRIHFB2122,LOC51051, C3F, LOC51086, P2Y10, RABEX5, RNASE3L, FJX1, SIG11, LOC64172,HS1-2, P2RY6, PC, PDHB, PDK3, QDPR, RABL2B, RAB11B, RAB33A, RAB38,RAB3IL1, RAB5B, RAB5C, GAPCENA, RAB6C, RAB7, RAB7L1, #80, RAB5EP,RAD23B, RAD51C, PIR51, RAD54L, RAD54B, RAD9, RSP3, RDX, RAE1, RALGPS1A,REPS2, LOC83859, RGL, RANBP1, RANBP6, EPAC, RAP1GDS1, RPIP8, RAMP,LOC54453, #81, ARHF, ARHH, RIN1, GAP11P4BP, RASAL1, RASAL2, RASGRF1,RREB1, G3BP, RIS1, RAC3, RRP22, LOC51655, RBAK, REST, RLF, RAMP3, RIPK1,RIPK2, RIPK3, RBPSUHL, RCV1, RECQL, RECQL4, RGPR, RGS14, RGS16, RGS8,RFX4, RFX5, RFXAP, RSC1A1, RNTRE, RENBP, RFC3, RFC4, RFC5, RIP60, RPA3,RSN, RFP, RFP2, RFPL2, RCN2, RTN2, RTN4, LOC51170, RP1, RP2, RPGR,RBBP1, RBBP4, RAIl, RAI15, RAI2, RARA, RARB, RARG, LOC51036, RXRG, RDH5,RDHL, RBP1, REV1L, REV3L, RECK, RGC32, RHAG, RTKN, RNASEH1, RNASEHI,RPP14, RPP38, RNASE1, RNASE4, RPN1, RPIA, RPL14, RPL19, RPL21, RPL23,RPL23A, RPL24, RPL26, RPL27, RPL4, RPL44, RPL8, RPS12, RPS14, RPS15,RPS21, RPS23, RPS25, RPS27A, RPS6 KB1, RPS6KA1, RPS6KA3, RPS6KA4, RIT,RING1, RNF17, RNF2, RNF20, RNF23, RNF24, RNF25, RNF30, RYBP, LOC51285,RNMT, RPC, RBM10, RBM7, RBM8A, RBM9, RBMS1, RBMS2, LOC84549, RNAHP,RNUT1, RNU17D, RNPS1, RMP, RU2, RUNX1, RUNX2, RUVBL1, RUVBL2, RYR2, RYK,S100A10, S100A12, S100A13, S100A3, S100A5, LOC57402, SAC2, AHCY, SAMHD1,SAMSN1, SARCOSIN, SBBI31, SAFB, SCHIP1, SOST, SEC10L1, SEC13L1, SEC22A,SEC22L1, SEC24A, FLJ10578, SEC61G, SFRP5, SCAMP3, SEL1L, SEPN1, SEMA3B,SEMA3C, SEMA4B, SEMA4D, SEMA4F, SEMA4G, SEMA4C, SEMG2, SENP2, 37137,SQSTM1, SERPINB4, SERPINB8, SERPIND1, SERPINE1, SERPINF2, SERPING1,SERPINH1, SR-A1, SDS, SHMT1, SPTLC2, SPINK5, SPINT1, SPINLW1, SRR, NDR,STK10, STK11, STK13, STK16, STK17A, STK17B, STK18, STK19, STK2, STK6,MST4, MGC4809, SDCCAG10, SDCCAG28, SDCCAG3, SDCCAG31, PK428, SES2,SETDB1, SET, SIAH2, SCML2, SRY, HSSEXGENE, SRPK1, SH2D2A, SPAP1, SH3BGR,SH3BGRL2, SH3BP2, SH3GL2, SH3GLB2, SHB, HRIHFB2072, SHOX2, HEP27, SIT,SIGLEC10, SIGLEC11, SIGLEC8, SIGLEC9, NEU2, SN, STHM, SIAT1, SIAT4B,SIAT4C, SIAT6, SIAT8D, SIAT8B, SIAT8A, SIAT8C, SIAT9, SRP19, SRPR, SSR1,SSR2, STAT2, STAT5A, STAT5B, STAT6, SIPA1, SLAM, SILV, #82, #83,LOC57168, KEO4, #84, #85, #86, MGC14386, #87, Rpo1-2, #88, #89,LOC92797, #90, #91, #92, #93, #94, #95, #96, #97, #98, #99, LOC91151,#100, #101, #102, #103, #104, #105, #106, #107, #108, #109, #110, #110,#112, LOC90522, #113, #114, #115, #116, #117, #118, #119, #120, #121,#122, #123, #124, #125, HS1119D91, LOC57167, #126, #126A, UPF3A, UPF3B,#127, #128, SAP30, SIX2, SIM1, SSBP2, SIRT2, SIRT5, SSA1, SSB, XP5,#129, SMA3, HspB9, SCYA1, SCYA3, SCYA4, SCYA5, SCYA16, SCYA18, SCYA20,SCYA22, SCYA24, SCYA8, SCYB10, SCYB14, SCYB6, SMP1, SNRPA1, SNRPE,SNRPF, SNRPG, SOLH, SHARP, SMCX, SMOH, SNAI1, SNAPAP, SRCAP, SCNN1A,SCNN1G, SLC1A6, SLC12A4, SLC12A6, SLC12A5, SLC13A3, SLC16A5, SLC18A2,SLC19A1, SLC2A1, SLC2A3, SLC2A6, SLC20A1, SLC21A12, SLC21A9, SLC22A8,SLC22A1, SLC22A1LS, SLC22A5, SLC24A3, SLC25A20, SLC25A5, SLC25A6,SLC25A10, SLC26A2, SLC27A4, SLC28A3, SLC29A1, SLC29A2, SLC3A2, SLC3A1,SLC30A1, SLC30A4, SLC4A1AP, SLC4A7, SLC4A10, SLC5A3, SLC6A8, SLC6A1,SLC6A13, SLC6A9, SLC6A7, SLC6A6, SLC7A10, SLC7A11, SLC9A1, SLC9A5,SSTR5, SON, SOS1, SORL1, SNX12, SNX15, SNX16, SNX2, HSSOX6, SP2, SP3,SPOCK, SATB1, SSH3BP1, SPTAN1, SPTBN1, SPAG1, SPAG4, SPAG9, #130, STRBP,SPATA2, SAT, SKP2, SMPD1, SPHK2, SF3A1, SF3A2, SF3B1, SF3B2, SFRS10,SFRS3, SFRS5, SFRS6, SFRS7, SPON2, SPR1, SPRY1, SPRY2, SART-2, SLA,SOX13, SOX2, SOX22, SOX4, SSI-3, STATI2, CIS4, STMN3, SLK, SCGF, SLU7,ZAK, SREBF1, SREBF2, STG, STOML1, STCH, STAG1, SDF1, STIM1, SNT-1, SDHC,SDHD, SUOX, SULT2B1, STE, SUSP1, SOD2, SVIL, ST5, ST7, SUFU, SKD1, SKD3,SURF5, SURF6, SMARCAL1, SMARCB1, SMARCD1, SMARCF1, SYNE-1B, SV2B,SYNGR4, SYTL2, SDC4, SS18, STX10, STX11, STX16, STX5A, STX7, STXBP1,STXBP2, SNTB1, TACTILE, TRA@, TRD@, TRG@, TAF9L, S1L, TBK1, TARBP1,TOM1L2, TAS2R13, TAS2R14, TAS2R7, TAF1C, TAF2A, TAF2C2, TAF2N, TAX1 BP1,TBX21, TBX6, TAL1, TIAM1, TCP10, TEKT3, TEX13A, TEX13B, FLJ20499,TSGA10, TSGA14, TSKS, TETRAN, TSPAN1, TIAF1, TGIF, TGIF2, TH1L, TPMT,AOE372, TXNRD1, TR2, THBD, THBS3, TK2, TRIP10, TRIP11, TRIP12, TRIP13,TRIP3, TRIP4, TRIP6, THRA, TRAP240, TRHR, TIA1, TIAL1, TIGA1, TJP2,TSTA3, TLH29, TRAF1, TRAF3, GG2-1, TLR1, TLR2, TOP2A, TOP3A, TOP3B,TRF4-2, TPARL, AD022, TANK, KIAA0057, ICBP90, TCF17, TCF19, TCF3,TCF6L1, TFAP4, TFE3, TFCP2, TFEC, NRF, TCFL1, TCFL4, TCFL5, TTF1, TTF2,CROC4, ALY, TIF1, TReP-132, TOB1, TLE4, TF, TFRC, HSU53209, TGFB1I1,TAB1, TGFA, TGFB1, TGFBR3, TGM3, TGM5, TRPC6, TERE1, GC20, IF2, TIM17,TIMM8A, TIMM8B, KIAA0016, TOMM70A, TRAM, #134, TLOC1, TM4SF1, TM4SF5,TM7SF2, TACl, TMG4, TMEM1, TMEM2, TMEM5, TMEM7, TMPIT, TMEFF1, TAP1,LOC58486, #135, RAP1, THH, TREM1, TNRC11, TNRC12, TNRC4, TPI1, TRIM14,TRIM22, TRIM26, TRIM33, TRIM34, TRIM5, TRIM6, TPP2, TR10, TFG, IPT,SECP43, TGT, TRO, TROAP, TMOD2, TMOD3, TPM1, TPM2, TPM4, LOC51149,WARS2, TSFM, TSPYL, TTK, TUFM, TULP3, TSC2, TUBA3, TUBB, TDRKH,PCTAIRE2BP, TUFT1, HCC8, TEM8, TNFSF13, TNFSF15, TNFSF7, TNFSF9, TNF,FIP2, TNFRSF10D, TNFRSF21, TNFRSF4, TNFRSF6, TNFRSF6B, TNFAIP1, TNFAIP2,TNFAIP3, TNFAIP6, TPD52L1, TP53BP1, DLM1, TSSC1, TSSC3, TUCAN, TSG, 1-4,PSK-1, TYRO3, TYRP1, YWHAE, YWHAH, YWHAG, T1E, U2AF65, HPRP8BP, LSM5,LOC51691, UQCRB, USP10, USP12, USP14, USP16, USP18, USP9X, UBE4A, UBE2A,UBE2C, UBE2E1, UBE2E3, UBE2H, UBE2L3, UBE2N, UBL1, UBL3, NEDD4L,B4GALT5, B3GNT5, B3GNT6, UGCGL2, UGDH, GALNT2, GNE, UAP1, ULBP3, BM036,MDS028, MDS030, MDS032, HARP11, HT007, HT008, VDUP1, UCC1, UBTF, UREB1,USF1, UNG2, UMPH1, UP, UCN, UPK2, HSHUR7SEQ, V1RL1, ABL1, ABL2, VPS26,VPS4, AKT2, VCP, VARS2, VANGL2, VR1, OTRPC4, VNN3, VCY2, VCAM1, VEGFC,VIP, VIPR1, CRK, CRKL, VAX2, ERBB3, VAMP1, VAMP4, ETS1, ETS2, FOS,SCAM-1, VMD2, VIT1, MYB, MYBL1, MYC, KIAA1329, BRAF, RALA, RALB, REL,RELA, RELB, SKI, YES1, WASF1, WDR10, WDR3, WDR4, WDF2, WDR11, WHIP,KIAA0105, WAS, WHSC2, WW45, WWOX, MDS009, XAGE-1, XBP1, XPR1, XPA,XPNPEP2, HSXQ280RF, XRCC2, YAF2, ZF5128, ZFP, ZNF-U69274, ZFD25, ZNF131,ZNF146, ZNF151, ZNF16, ZNF165, ZNF185, ZNF187, ZNF19, ZNF193, ZNF195,ZNF200, ZNF205, ZNF213, ZNF22, ZNF221, ZNF230, ZNF236, ZNF237, ZNF238,ZNF257, ZNF258, ZNF26, ZNF264, ZNF268, ZNF278, ZNF297, ZNF302, ZNF313,ZNF33B, ZNF36, ZNF44, ZNF45, ZNF79, ZNF83, ZNF85, ZNF9, ZNF91, ZFP161,ZNFN1A1, PEGASUS, ZFX, ZNRD1, ZHX1, ZYG and ZYX. Homologs of these genesor proteins in other species, e.g., primates, are also modulated by theF1C. Modulation of these genes can be observed, e.g., as increasedexpression or mRNA levels or protein levels of the biomolecules inclinical conditions where insufficient or suboptimal expression orlevels of the gene is associated with establishment, maintenance,severity or progression of the clinical condition to produce a desiredclinical improvement.

Other therapeutic and biological applications and activities. The F1Csare useful for preventing, slowing the progression of or treatingcertain chronic conditions in a subject such as a mammal or a human.Chronic conditions include diseases and conditions that arise or developover a relatively long time period, e.g., over about 3 months to 10years or more. Such conditions include chronic renal failure, which mayresult from polycystic kidney disease, from, e.g., an autoimmunecondition such as acute or chronic glomerulonephritis, or from diabetes,interstitial nephritis, hypertension and other conditions discussedelsewhere herein. Chronic conditions include chronic pulmonaryconditions such as chronic bronchitis, lung fibrosis, right ventricularhypertrophy, pulmonary hypertension, emphysema, asthma and chronicobstructive pulmonary disease, which may be treated with a F1C. Theseconditions or their symptoms may be mild, moderate or severe. Thesubject may be suffering from the disease or condition or may be subjectto developing the condition, e.g., the subject may display early signsor a predisposition to develop a chronic condition. Such treatment willgenerally facilitate prevention of the disease, delay the onset orseverity of the disease or condition, ameliorate one or more symptoms,e.g., reduce shortness of breath, coughing or dyspnea, or slowprogression of the disease or condition. In these and other chronicconditions described herein, the F1Cs will generally be administered toa subject such as a human for a relatively long time period, e.g., forat least about 3 months to about 10 years or more. Dosages, routes ofadministration and dosing protocols for the F1Cs are essentially asdescribed herein. Dosing of the compound can be daily or intermittentusing a dosing protocol using dosages as described herein, e.g., about0.1 to about 20 mg/kg of a F1C administered to a subject once or twiceper day daily or intermittently. The use of the F1Cs can be combinedwith other treatments, e.g., β-agonists such as metaproterenol oralbuterol, or corticosteroids, e.g., prednisone, for asthma or chronicobstructive pulmonary disease.

The F1Cs can modulate the biological activity of cytokines orinterleukins that are associated with various immune deficiency ordysregulation conditions, which may be transient or chronic. They canthus be used to ameliorate, treat or prevent naturally occurringage-related decline in immune function in a subject or immune deficiencyor dysregulation resulting from trauma, stress, burns, surgery,autoimmunity or infections as described herein. Such immune deficiencydysregulation may be associated with, e.g., an age-related increase inproduction of one or more of IL-4, IL-5 and IL-6 or an age-relateddecrease in production of one or more of IL-2, IL-3, Y-IFN, GM-CSF orantibodies. In these embodiments, the F1C is administered to the subjectto detectably decrease production or levels of one or more of IL-4, IL-5and IL-6 or to detectably increase production or levels of one or moreof IL-2, IL-3, IL-5, IL-12, GM-CSF and Y-IFN. These cytokine changesfacilitate normalization of the subject's immune responses. Suchnormalization can be observed by various means. These means includemonitoring appropriate cytokine RNA or protein level(s) in the subjector by measuring biological responses such as restoration or detectableimprovement of contact hypersensitivity in a subject with depressed orsuboptimal contact hypersensitivity response. The F1Cs can thus be usedto enhance or restore a deficient or suboptimal immune response such ascontact hypersensitivity response in a subject with a chronic ortransient state of immune deficiency or dysregulation. In theseembodiments, the F1C is administered using the dosages, routes ofadministration and dosing protocols for the F1Cs essentially asdescribed herein. Treatment with the F1Cs is optionally combined withother appropriate treatments or therapies essentially as describedherein, e.g., a antibacterial or antiviral agent(s) is coadministeredwith a F1C to treat, prevent or ameliorate an infection in an infectedsubject or a subject suffering from, e.g., a burn. Methods to measurechanges in cytokine levels or contact hypersensitivity are known and canoptionally be applied in these embodiments, see, e.g., U.S. Pat. Nos.5,919,465, 5,837,269, 5,827,841, 5,478,566.

The capacity of the F1Cs to modulate immune functions permits their usefor treating, preventing, slowing the progression of or alleviating thea symptom(s) of subjects with psychological disorders, metabolicdisorders, chronic stress, sleep disorders, conditions associated withsexual senescence, aging, or premature aging. Metabolic disordersinclude parathyroidism, pseudoparathyroidism, hypoparathyroidism,hypercalcemia, hypocalcemia and detectable symptoms thereof such asfatigue, constipation, kidney stones and kidney malfunction. Chronicstress and related disorders include fibromyalgia, chronic fatiguesyndrome, hypothalamic-pituitary axis dysregulation. Other relatedpathological conditions that can be treated with the F1Cs includehormone deficiency associated with aging or with a pathologicalcondition, hypogonadism, vaginal atrophy, diminished libido, urinaryincontinence, skin collagen loss, loss or impairment of skin, organ orjoint connective tissue and menopause or its symptoms such as hotflashes, unwanted mood changes, fatigue and insomnia. In theseembodiments, treatment of subjects with a F1C is optionally combinedwith other suitable agents such as triiodothyronine, tetraiodothyronine,an insulin-like growth factor, insulin-like growth factor bindingprotein-3, an estrogen or a progestin.

As noted above, in some embodiments a treatment with a F1C is combinedwith a corticosteroid or glucocorticoid. Corticosteroids are used in anumber of clinical situations to, e.g., decrease the intensity orfrequency of flares or episodes of inflammation or autoimmune reactionsin conditions such as acute or chronic rheumatoid arthritis, acute orchronic osteoarthritis, ulcerative colitis, acute or chronic asthma,bronchial asthma, psoriasis, systemic lupus erythematosus, hepatitis,pulmonary fibrosis, type I diabetes, type II diabetes or cachexia.However, many corticosteroids have significant side effects ortoxicities that can limit their use or efficacy. The F1Cs are useful tocounteract such side effects or toxicities without negating all of thedesired therapeutic capacity of the corticosteroid. This allows thecontinued use, or a modified dosage of the corticosteroid, e.g., anincreased dosage, without an intensification of the side effects ortoxicities or a decreased corticosteroid dosage. The side-effects ortoxicities that can be treated, prevented, ameliorated or reducedinclude one or more of bone loss, reduced bone growth, enhanced boneresorption, osteoporosis, immunosuppression, increased susceptibility toinfection, mood or personality changes, depression, headache, vertigo,high blood pressure or hypertension, muscle weakness, fatigue, nausea,malaise, peptic ulcers, pancreatitis, thin or fragile skin, growthsuppression in children or preadult subjects, thromboembolism,cataracts, and edema. Dosages, routes of administration and dosingprotocols for the F1C would be essentially as described herein. Anexemplary dose of F1C of about 0.5 to about 20 mg/kg/day is administeredduring the period during which a corticosteroid is administered andoptionally over a period of about 1 week to about 6 months or more afterdosing with the corticosteroid has ended. The corticosteroids areadministered essentially using known dosages, routes of administrationand dosing protocols, see, e.g., Physicians Desk Reference 54^(th)edition, 2000, pages 323-2781, ISBN 1-56363-330-2, Medical EconomicsCo., Inc., Montvale, N.J. However, the dosage of the corticosteroid mayoptionally be adjusted, e.g., increased about 10% to about 300% abovethe normal dosage, without a corresponding increase in all of the sideeffects or toxicities associated with the corticosteroid. Such increaseswould be made incrementally over a sufficient time period and asappropriate for the subject's clinical condition, e.g., dailycorticosteroid dose increases of about 10% to about 20% to a maximum ofabout 300% over about 2 weeks to about 1 year.

Such corticosteroids include hydrocortisone (cortisol), corticosterone,aldosterone, ACTH, triamcinolone and derivatives such as triamcinolonediacetate, triamcinolone hexacetonide, and triamcinolone acetonide,betamethasone and derivatives such as betamethasone dipropionate,betamethasone benzoate, betamethasone sodium phosphate, betamethasoneacetate, and betamethasone valerate, flunisolide, prednisone,fluocinolone and derivatives such as fluocinolone acetonide, diflorasoneand derivatives such as diflorasone diacetate, halcinonide,dexamethasone and derivatives such as dexamethasone dipropionate anddexamethasone valerate, desoximetasone (desoxymethasone), diflucortoloneand derivatives such as diflucortolone valerate), flucloroloneacetonide, fluocinonide, fluocortolone, fluprednidene, flurandrenolide,clobetasol, clobetasone and derivatives such as clobetasone butyrate,alclometasone, flumethasone, and fluocortolone.

In some applications, the F1C(s) may directly and/or indirectlyinterfere with replication, development or cell to cell transmission ofa pathogen such as a virus or a parasite (malaria). Improvement in asubject's clinical condition may arise from a direct effect on aninfectious agent or on a malignant cell. Interference with cellularreplication can arise from inhibition of one or more enzymes that aparasite or an infected cell uses for normal replication or metabolism,e.g., glucose-6-phosphate dehydrogenase, which affects cellulargeneration of NADPH (see, e.g., Raineri et al., Biochemistry 1970 9:2233-2243). This effect may contribute to cytostatic effects that someF1Cs can have. Modulation of cellular enzymes expression or activity mayalso interfere with replication or development of a pathogen, e.g., HIVor malaria parasites or with replication or development of neoplasticcells, e.g., inhibition of angiogenesis. Clinical improvement will alsogenerally result from an enhanced immune response such as an improvedTh1 response.

Administration of a F1C can lead to a decrease in adenosine levels in asubject's tissue(s), e.g., lung or central nervous system tissue. Thiseffect can be used to treat, prevent, ameliorate one or more symptoms ofor slow the progression of a disease(s) or clinical condition(s) where arelatively high level of adenosine is a factor in or can contribute tothe disease or condition, e.g., in asthma.

Adenosine is associated with the symptoms of bronchial asthma, where itcan induce bronchoconstriction or contraction of airway smooth muscle inasthmatic subjects, see, e.g., J. Thorne and K. Broadley, AmericanJournal of Respiratory & Critical Care Medicine 149(2 pt. 1):392-3991994, S. Ali et al., Agents & Actions 37:165-167 1992, Bjorck et al.,American Review of Respiratory Disease 145:1087-1091 1992. This effectis not observed in non-asthmatic subjects. In the central nervoussystem, adenosine can inhibit the release of neurotransmitters such asacetylcholine, noradrenaline, dopamine, serotonin, glutamate, and GABA.It can also depress neurotransmission, reduce neuronal firing to inducespinal analgesia and it possesses anxiolytic properties, see, e.g., A.Pelleg and R. Porter, Pharmacotherapy 10:157 1990. In the heart,adenosine suppresses pacemaker activity, slows AV conduction, possessesantiarrhythmic and arrhythmogenic effects, modulates autonomic controland triggers the synthesis and release of prostaglandins. In addition,adenosine has vasodilatory effects and can modulate vascular tone.

The unwanted effects of excess adenosine can be ameliorated or reducedby administering sufficient amounts of a F1C to a subject who is subjectto developing or who has an unwanted level of adenosine in one or moretissues or organs. In typical embodiments, one will administer about 10mg/kg/day to about 100 mg/kg/day of a F1C to a subject over a period ofabout 1 week to about 4 months to effect detectable changes in adenosinelevels or amelioration in one or more symptoms associated with highadenosine in one or more of the subject's tissues. Such changes may bedetermined by comparing the subject's adenosine levels before treatmentwith the F1C is started. Alternatively, for subjects with symptoms thatare consistent with high adenosine levels, the decrease can be inferredby comparing the normal level of adenosine in the target tissue(s) forsubjects of the same species and similar age or sex with the level thatis observed after treatment. Methods to measure adenosine levels inmammalian tissue are known and can optionally be used in theseembodiments, e.g., U.S. Pat. No. 6,087,351.

In some clinical conditions, the F1Cs can inhibit activated Tlymphocytes in vivo, and they can inhibit the expression or biologicalactivity of one or more of TNF-α, IFN-γ, IL-6, IL-8 or insulin likegrowth factor-1 receptor (IGF-1R) or IL-6 receptor. The compounds arethus useful to treat, prevent or ameliorate conditions where this is acomponent of pathology. Such conditions include inflammation conditionssuch as psoriasis, psoriatic arthritis, osteoarthritis, and rheumatoidarthritis. The compound can thus ameliorate the inflammation, e.g., byinhibiting expression of one or more of TNF-α, IFN-γ, IL-6, IL-8 orIGF-1R. Also, the compounds can inhibit unwanted T cell activity. Theycan thus ameliorate one or more psoriasis symptoms such as skin scaling,skin thickening, keratinocyte hyperproliferation, deficient filaggrinexpression (B. Baker et al., Br. J. Dermatol. 1984, 111:702), deficientstrateum corneum lipid deposition or they can improve a clinicalassessment such as the Psoriasis Activity and Severity Index. The F1Cscan be delivered to a subject with psoriasis using topical or systemicformulations as described herein. Topical formulations include gels,lotions and creams, e.g., as described herein. Daily or intermittentadministration of the compound can be used essentially as describedherein. The use of the F1Cs is optionally combined with one more currentpsoriasis treatments, e.g., topical emollients or moisturizers, tars,anthralins, systemic or topical corticosteroids, vitamin D analogs suchas calcitriol, methotrexate, etretinate, acitretin, cyclosporin, FK 506,sulfasalazine, ultraviolet B radiation optionally combined with one ormore of a topical corticosteroid, tar, anthralin, emollient ormoisturizer or ultraviolet A plus psoralen. Such additional treatmentsessentially would use known dosages and routes of administration, whichare applied, e.g., within a month before, during or within a month aftera treatment course with a F1C.

Other desirable modulation effects of the F1Cs on cells or tissuesinclude (1) inhibition of one or more of bone resorption or calciumrelease or gp80, gp130, tumor necrosis factor (TNF), osteoclastdifferentiation factor (RANKL/ODF), RANKL/ODF receptor, IL-6 or IL-6receptor expression or biological activity in, e.g., bone loss orosteoporosis conditions or in osteoclasts, or in cancers such asprostate cancer, metastatic breast cancer or metastatic lung cancer(e.g., with bone metastases), (2) inhibition of osteoclastogenesis orosteoclast development from progenitor cells, (3) enhancement of NFκBinhibition that is mediated by nuclear hormone receptors, e.g., enhancedinhibition of estrogen receptor-α or estrogen receptor-β mediatedinhibition of NFκB in inflammation, rheumatoid arthritis orosteoporosis, (4) enhancement of osteoblastogenesis, osteoblast, bonecallus or bone development, e.g., from progenitor cells in bonefractures, depressed bone healing situations (e.g., in a burn patient orin a patient being treated with a glucocorticoid), bone growth orosteoporosis or other bone loss conditions, by, e.g., modulation orenhancement of osteoblast replication or development or modulation orenhancement of the synthesis or biological activity of a transcriptionfactor such as Cbfa1, RUNX2 or AML-3 (5) normalization ofhypothalamic-pituitary-adrenal axis function in conditions where thereis dysregulation such as in chronic inflammatory diseases, chronicasthma or rheumatoid arthritis (increased cortisol to ACTH ratio), (6)modulation of ligand-gated ion channels in neurons in, e.g., depression,sleep or memory disorders, (8) modulation of G-protein coupled receptorsin neurons in, e.g., depression, sleep or memory disorders, (9)modulation, e.g., induction or inhibition, of the synthesis orbiological activity of metabolic enzymes such as a cytochrome or ahydroxylase (e.g., 11β hydroxylase, a CYP enzyme such as CYP1A1, CYP2B1,CYP2b10, CYP4A, CYP7A, CYP7A1, CYP7B, CYP7B1, CYP11A1, CYP11B1, CYP17,P450 3A4, P450c17, P450scc, P450c21 or an isozyme, homolog or mutant ofany of these) in cells or tissues such as liver cells, neurons, neuronprecursor cells, brain, breast, testes or colon, (10) enhancement ofcollagen synthesis or levels in, e.g., skin in aging or skin damagefrom, e.g., trauma, thermal injury or solar radiation, (11) inhibitionof nitric oxide production in cells or tissue, e.g., in nervous systemtissue or in microglial cells in dementias such as Alzheimer's disease,(12) enhancing glucose-stimulated insulin synthesis in hyperglycemia ordiabetes conditions, (13) modulation of gamma-aminobutyric acid (GABA),dopamine or N-methyl-D-aspartate (NMDA) receptor activity or levels in,e.g., brain tissue or neurons, (e.g., decreased GABA-mediated chloridecurrents or potentiation of neuronal response to NMDA in thehippocampus) in, e.g., conditions such as a dementia (Alzheimer'sDisease), depression, anxiety, schizophrenia or memory loss due to,e.g., aging or another condition described herein, (14) modulating(e.g., enhancing) the expression or activity of a transcriptionfactor(s), or a homolog(s) or isoform(s), such as SET, nerve growthfactor inducible protein B, StF-IT, SF-1 in cells or tissues such asnerve cells, neuronal precursor cells or liver cells, (15) inhibition ofeosinophil infiltration or reduction IgE levels in allergic responses orin lung or other tissue, (16) modulation, e.g., a decrease, in serum orblood of leptin levels in, e.g., obese subjects such as humans with abody mass index of about 27, 28, 29, 30, 31, 32, 33, 34 or greater, (17)increased corticotropin releasing hormone synthesis or activity in,e.g., elderly subjects such as humans at least about 60 years of age orat least about 70 years of age, (18) enhancement of memory or reductionof memory loss or disorientation in aging or dementias such asAlzheimer's Disease, (20) enhancement of the synthesis or activity ofone or more enzymes responsible for thermogenesis, e.g., liverglycerol-3-phosphate dehydrogenase or malic enzyme, in subjects such asobese or diabetic humans, (21) modulation, e.g., reduction, of thesynthesis or biological activity of the CXCR4 receptor or the CXCL12chemokine in hyperproliferation conditions such as breast cancers orprecancers, (22) modulation of the synthesis or biological activity ofone or more of holocytochrome c, cytochrome c, secondmitochondria-derived activator of caspase, Apaf-1, Bax, procaspase-9,caspase-9, procaspase-3, caspase-3, caspase-6 and caspase-7, e.g.,enhanced translocation of these molecules from mitochondria to cytosolor activation of these molecules in the cytosol in cancer precancercells, cancer cells or cells that mediate autoimmunity, (23) modulationof the synthesis or biological activity of one or more of tumor necrosisfactor-α, interleukin-1β converting enzyme, IL-6, IL-8, caspase-4 andcaspase-5, e.g., decreased activation of these molecules in injuredcells or cells subject to injury from, e.g., ischemia or infarction(e.g., vascular, cardiac or cerebral), reperfusion of hypoxic cells ortissue or an inflammation condition such as rheumatoid arthritis,ulcerative colitis, viral hepatitis, alcoholic hepatitis, or anotherinflammation condition disclosed herein, (24) decrease of the synthesis,biological activity or activation of one or more of phospholipase A2,caspase-1, caspase-3 and procaspase-3 in neurodegeneration disorders ordementias such as Alzheimer's disease, Huntington's disease, or anotherneurological condition disclosed herein, (25) regulation ornormalization of dysregulated protein kinase B, phosphatidylinositol3-kinase and Forkhead transcription factors, e.g., a class 0 Forkheadtranscription factor, in immune dysregulation or oxidative stressconditions such as immune suppression, allergy or autoimmune conditions.The F1Cs can thus be used where one or more of these conditions or theirsymptoms is present. Methods to measure the synthesis or biologicalactivity of these molecules has been described, see, e.g., U.S. Pat.Nos. 6,200,969, 6,187,767, 6,174,901, 6,110,691, 6,083,735, 6,024,940,5,919,465 and 5,891,924.

Specific Embodiments. Aspects of the invention and related subjectmatter include the following specific embodiments.

1. A method to prevent, treat, ameliorate or slow the progression ofcystic fibrosis, sickle cell disease, neutropenia or thrombocytpoenia ina subject, or to treat a symptom of the neutropenia or thrombocytopenia,comprising administering to a subject, or delivering to the subject'stissues, an effective amount of a formula 1 compound having thestructure 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14

or a metabolic precursor or a metabolite thereof, wherein

R¹⁰ moieties at the 5 (if present), 8, 9 and 14 positions respectivelyare in the α,α,α,α, α,α,α,β, α,α,β,α, α,β,α,α, β,α,α,α, α,α,β,β,α,β,α,β, β,α,α,β, β,α,β,α, β,β,α,α, α,β,β,α, α,β,β,β, β,α,β,β, β,β,α,β,β,β,β,α or β,β,β,β configurations,

wherein R^(10A), R^(10B), R^(10C), R^(10D) and R^(10E) respectively arein the α,α, α,β, β,αor β,β configurations,

wherein, each R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰, R^(10A), R^(10B), R^(10C),R^(10D) and R^(10E) independently are —H, —OH, —OR^(PR), —SR^(PR),—N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN, —NO₂, —NH₂, —COOH,—OSO₃H, —OPO₃H, an ester, a thioester, a thionoester, a phosphoester, aphosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, asulfate ester, an amide, an amino acid, a peptide, an ether, athioether, an acyl group, a thioacyl group, a carbonate, a carbamate, ahalogen, an optionally substituted alkyl group, an optionallysubstituted alkenyl group, an optionally substituted alkynyl group, anoptionally substituted aryl moiety, an optionally substituted heteroarylmoiety, an optionally substituted heterocycle, an optionally substitutedmonosaccharide, an optionally substituted oligosaccharide, a nucleoside,a nucleotide, an oligonucleotide, a polymer, or,

one more of R¹, R², R³, R⁴, R⁵, R⁶, R¹⁰, R^(10A), R^(10B), R^(10C),R^(10D) and R^(10E) are ═O, ═S, ═N—OH, ═CH₂, ═CH—CH₃, or anindependently selected spiro ring and the hydrogen atom or the secondvariable group that is bonded to the same carbon atom is absent, or,

one or more of two adjacent R¹-R⁶, R¹⁰, R^(10A), R^(10B), R^(10C),R^(10D) and R^(10E) comprise an independently selected epoxide, acetal,a thioacetal, ketal or thioketal;

R⁷ is —C(R¹⁰)₂—, —C(R¹⁰)₂—C(R¹⁰)₂—, —C(R¹⁰)₂—C(R¹⁰)₂—C(R¹⁰)₂—,—C(R¹⁰)₂—O—C(R¹⁰)₂—, —C(R¹⁰)₂—S—C(R¹⁰)₂—, —C(R¹⁰)₂—NR^(PR)—C(R¹⁰)₂—,—O—, —O—C(R¹⁰)₂—, —S—, —S—C(R¹⁰)₂—, —NR^(PR)— or —NR^(PR)—C(R¹⁰)₂—;

R⁸ and R⁹ independently are —C(R¹⁰)₂—, —C(R¹⁰)₂—C(R¹⁰)₂—, —O—,—O—C(R¹⁰)₂—, —S—, —S—C(R¹⁰)₂—, —NR^(PR)— or —NR^(PR)—C(R¹⁰)₂—, or one orboth of R⁸ or R⁹ independently are absent, leaving a 5-membered ring;

R¹³ independently is C₁₋₆ alkyl; and

R^(PR) independently is —H or a protecting group, optionally providedthat (1) one or two of R^(10A), R^(10B), R^(10C), R^(10D) and R^(10E)are not hydrogen or (2) one R⁴ is —NH₂ an opotionally substituted amine,—N(R^(PR))², ═NOH, ═NO-optionally substituted alkyl, an amide or anN-linked amino acid. In these embodiments, the subject may have or besubject to developing the listed condition and the subject can be ahuman or a primate.

2. The method of embodiment 1 wherein one each of R¹, R², R³ and R⁴ are—H, and, when no double bond links the second R¹, R², R³ and R⁴ to thering to which it is bonded and no double bond is present at the 16-17position, then the second R¹, R², R³ and R⁴ respectively are in theα,α,α,α, α,α,α,β, α,α,β,α, α,β,α,α, β,α,α,α, α,α,β,β, α,β,α,β, β,α,α,β,β,α,β,α, β,β,α,α, α,β,β,α, α,β,β,β, β,α,β,β, β,β,α,β, β,β,β,α o rβ,β,β,β configurations and the second R¹, R², R³ and R⁴ are optionallyindependently selected from —H, —F, —Cl, —Br, —I, —OH, —SH, —NH₂, —COOH,—CH₃, —C₂H₅, —C(CH₃)₃, —OCH₃, —OC₂H₅, —CF₃, —CH₂OH, —C(O)CH₃,—C(O)CH₂OH, —C(O)CH₂F, —C(O)CH₂Cl, —C(O)CH₂Br, —C(O)CH₂I, —C(O)CF₃,—C₂F₅, ═O, ═CH₂, ═CHCH₃, amino acid, carbamate, carbonate, optionallysubstituted C1-C20 alkyl, optionally substituted C1-C20 ether,optionally substituted C1-C20 ester, optionally substituted C1-C20thioether, optionally substituted C1-C20 thioester, optionallysubstituted monosaccharide, optionally substituted disaccharide,optionally substituted oligosaccharide.

3. The method of embodiment 1 or 2 wherein

(a) R^(10A) is bonded to the ring to which it is attached by a singlebond and a double bond is present at (i) the 1-2 position, or (ii) the1-2 and 16-17 positions; or

(b) R^(10B) is bonded to the ring to which it is attached by a singlebond and a double bond is present at the 4-5 position; or

(c) R^(10c) is bonded to the ring to which it is attached by a singlebond and a double bond is present at the 5-6 position; or

(d) R^(10A) and R^(10B) are bonded to the rings to which they areattached by a single bond and a double bond is present at (i) the 1-2and 4-5 positions, or (ii) the 1-2, 4-5 and 16-17 positions;

(e) R^(10A) and R^(10C) are bonded to the rings to which they areattached by a single bond and a double bond is present at (i) the 1-2and 5-6 positions, or (ii) the 1-2, 5-6 and 16-17 positions; or

(f) no double bond is present.

4. The method of embodiment 1, 2 or 3 wherein the compounds of structure5, 6, 7, 8, 9, 10, 11 and 12 have the structure

provided that if a double bond is present at the 1-2, 4-5 or 5-6positions, then R^(10A), R^(10B) or R^(10C) respectively are bonded tothe ring to which they are linked by a single bond and wherein, when R¹,R², R³ and R⁴ are single bonded, one is in the α-configuration and theother R¹, R², R³ and R⁴ is in the β-configuration.

5. The method of embodiment 1, 2, 3 or 4 wherein (1) R⁵ and R⁶respectively are in the α,α, α,β, β,α or β,β configuration and R⁵ and R⁶are optionally both —CH₃ or are optionally selected from —CH₃ and —CH₂OHor (2) R⁵ and R⁶ are both in the β-configuration and R⁵ and R⁶ areoptionally both —CH₃ or are optionally —CH₃ and —CH₂OH.

6. The method of embodiment 1, 2, 3, 4 or 5 wherein R⁵ and R⁶ areoptionally both in the β-configuration and are optionally independentlyselected from —H, —F, —Br, —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂CH₂OH, —CH(O),—CH₂OH, —CH₂-ester, —CH₂-ether, —CH₂-amino acid, —CH₂-carbamate,—CH₂OR^(PR), —CHS, —CH₂SH, —CH₂SR^(PR), —CH₂-thioester, —CH₂-thioether,—CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)_(n)—CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)_(n)—C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)_(n)—NHR^(PR), a monosaccharide, and an ester wherein nis 0, 1, 2, 3 or 4 and R^(PR) are independently selected protectinggroups for atoms to which they are bonded.

7. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein one each of R¹,R², R³ and R⁴ are —H and wherein (i) no double bond is present at the16-17 position, the second R¹, R², R³ and R⁴ respectively are bonded tothe ring to which they are attached by a single bond in the β,β,α,βconfigurations (i.e., R¹ is in the β-configuration, R² is in theβ-configuration, R³ is in the α-configuration and R⁴ is in theβ-configuration when no double bond is present at 16-17), or (ii) adouble bond is present at the 16-17 position and R¹ and R² respectivelyare in the β,β configurations (i.e., R¹ is in the β-configuration and R²is in the β-configuration when a double bond is present at 16-17).

8. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the β,β,β,βconfigurations or (ii) one each of R¹, R² and R³ are —H, no double bondis present at the 16-17 position, the second R¹, R² and R³ respectivelyare bonded to the ring to which they are attached by a single bond inthe β,β,β, β,β,α, β,α,β, α,β,β, β,α,α, α,β,α, α,α,β or α,α,αconfigurations and both R⁴ together are bonded to the ring by a doublebond (i.e., both R⁴ together are a double bonded moiety described hereinsuch as ═O, ═NOH, ═CH₂ or ═CH—CH₃).

9. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the β,β,β,αconfigurations or (ii) one each of R¹, R² and R⁴ are —H, no double bondis present at the 16-17 position, the second R¹, R² and R⁴ respectivelyare bonded to the ring to which they are attached by a single bond inthe β,β,β, β,β,α, β,α,β, α,β,β, β,α,α, α,β,α, α,α,β or α,α,αconfigurations and both R³ together are bonded to the ring by a doublebond (i.e., both R³ together are a double bonded moiety described hereinsuch as ═O, ═NOH, ═CH₂ or ═CH—CH₃).

10. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein no double bondis present at the 16-17 position, one each of R¹, R², R³ and R⁴ are —Hand the second R¹, R², R³ and R⁴ respectively are bonded to the ring towhich they are attached by a single bond in the β,β,α,α configurations.

11. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, the second R¹, R², R³ and R⁴ respectively are bonded to the ring towhich they are attached by a single bond in the β,α,β,β configurations(i.e., R¹ is in the β-configuration, R² is in the α-configuration, R³ isin the β-configuration and R⁴ is in the β-configuration when no doublebond is present at 16-17), or (ii) a double bond is present at the 16-17position and R¹ and R² respectively are in the β,α configurations (i.e.,R¹ is in the β-configuration and R² is in the α-configuration when adouble bond is present at 16-17).

12. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the β,α,β,αconfigurations or (ii) one each of R¹, R³ and R⁴ are —H, no double bondis present at the 16-17 position, the second R¹, R³ and R⁴ respectivelyare bonded to the ring to which they are attached by a single bond inthe β,β,β, β,β,α, β,α,β, α,β,β, β,α,α, α,β,α, α,α,β or α,α,αconfigurations and both R² together are bonded to the ring by a doublebond (i.e., both R² together are a double bonded moiety described hereinsuch as ═O, ═NOH, ═CH₂ or ═CH—CH₃).

13. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the β,α,α,βconfigurations or (ii) one each of R², R³ and R⁴ are —H, no double bondis present at the 16-17 position, the second R², R³ and R⁴ respectivelyare bonded to the ring to which they are attached by a single bond inthe β,β,β, β,β,α, β,α,β, α,β,β, β,α,α, α,β,α, α,α,β or α,α,αconfigurations and both R¹ together are bonded to the ring by a doublebond (i.e., both R¹ together are a double bonded moiety described hereinsuch as ═O, ═NOH, ═CH₂ or ═CH—CH₃).

14. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein no double bondis present at the 16-17 position, one each of R¹, R², R³ and R⁴ are —H,and the second R¹, R², R³ and R⁴ respectively are bonded to the ring towhich they are attached by a single bond in the β,α,α,α configurations.

15. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, the second R¹, R², R³ and R⁴ respectively are bonded to the ring towhich they are attached by a single bond in the α,β,β,β configurations(i.e., R¹ is in the α-configuration, R² is in the β-configuration, R³ isin the β-configuration and R⁴ is in the β-configuration when no doublebond is present at 16-17), or (ii) a double bond is present at the 16-17position and R¹ and R² respectively are in the α,β configurations (i.e.,R¹ is in the α-configuration and R² is in the β-configuration when adouble bond is present at 16-17).

16. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the α,β,α,βconfigurations or (ii) one each of R¹ and R³ are —H, no double bond ispresent at the 16-17 position, the second R¹ and R³ respectively arebonded to the ring to which they are attached by a single bond in theβ,β, β,α, α,β or α,α configurations and both R² together and both R⁴together are bonded to the ring by a double bond (i.e., both R² togetherand both R⁴ together are an independently selected double bonded moietydescribed herein such as ═O, ═NOH, ═CH₂ or ═CH—CH₃).

17. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the α,β,β,αconfigurations or (ii) one each of R² and R³ are —H, no double bond ispresent at the 16-17 position, the second R² and R³ respectively arebonded to the ring to which they are attached by a single bond in theβ,β, β,α, ≢,β or α,α configurations and both R¹ together and both R⁴together are bonded to the ring by a double bond (i.e., both R¹ togetherand both R⁴ together are an independently selected double bonded moietydescribed herein such as ═O, ═NOH, ═CH₂ or ═CH—CH₃).

18. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein no double bondis present at the 16-17 position, one each of R¹, R², R³ and R⁴ are —H,and the second R¹, R², R³ and R⁴ respectively are bonded to the ring towhich they are attached by a single bond in the α,β,α,α configurations.

19. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, the second R¹, R², R³ and R⁴ respectively are bonded to the ring towhich they are attached by a single bond in the α,α,β,β configurations(i.e., R¹ is in the α-configuration, R² is in the α-configuration, R³ isin the β-configuration and R⁴ is in the β-configuration when no doublebond is present at 16-17), or (ii) a double bond is present at the 16-17position and R¹ and R² respectively are in the α,α configurations (i.e.,R¹ and R² are both in the α-configuration when a double bond is presentat 16-17).

20. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the α,α,α,βconfigurations or (ii) one each of R¹ and R⁴ are —H, no double bond ispresent at the 16-17 position, the second R¹ and R⁴ respectively arebonded to the ring to which they are attached by a single bond in theβ,β, β,α, α,β or α,α configurations and both R² together and both R³together are bonded to the ring by a double bond (i.e., both R² togetherand both R³ together are an independently selected double bonded moietydescribed herein such as ═O, ═NOH, ═CH₂ or ═CH—CH₃).

21. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the α,α,β,αconfigurations or (ii) one each of R² and R⁴ are —H, no double bond ispresent at the 16-17 position, the second R² and R⁴ respectively arebonded to the ring to which they are attached by a single bond in theβ,β, β,α, α,β or α,α configurations and both R¹ together and both R³together are bonded to the ring by a double bond (i.e., both R¹ togetherand both R³ together are an independently selected double bonded moietydescribed herein such as ═O, ═NOH, ═CH₂ or ═CH—CH₃).

22. The method of embodiment 1, 2, 3, 4, 5 or 6 wherein (i) no doublebond is present at the 16-17 position, one each of R¹, R², R³ and R⁴ are—H, and the second R¹, R², R³ and R⁴ respectively are bonded to the ringto which they are attached by a single bond in the α,α,α,αconfigurations or (ii) one each of R¹ and R² are —H, no double bond ispresent at the 16-17 position, the second R¹ and R² respectively arebonded to the ring to which they are attached by a single bond in theβ,β, β,α, α,β or α,α configurations and both R³ together and both R⁴together are bonded to the ring by a double bond (i.e., both R³ togetherand both R⁴ together are an independently selected double bonded moietydescribed herein such as ═O, ═NOH, ═CH₂ or ═CH—CH₃) or (iii) one each ofR³ and R⁴ are —H, no double bond is present at the 16-17 position, thesecond R³ and R⁴ respectively are bonded to the ring to which they areattached by a single bond in the β,β, β,α, α,β or α,α configurations andboth R¹ together and both R² together are bonded to the ring by a doublebond (i.e., both R¹ together and both R² together are an independentlyselected double bonded moiety described herein such as ═O, ═NOH, ═CH₂ or═CH—CH₃).

23. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the α,β,α,α configurations or, if a doublebond is present at the 4-5 or the 5-6 positions, then R¹⁰ at the 8, 9and 14 positions respectively are in the β,α,α configurations.

24. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the β,β,α,α configurations.

25. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the α,β,α,β configurations or, if a doublebond is present at the 4-5 or the 5-6 positions, then R¹⁰ at the 8, 9and 14 positions respectively are in the β,α,β configurations.

26. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the β,β,α,β configurations.

27. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the α,β,β,α configurations or, if a doublebond is present at the 4-5 or the 5-6 positions, then R¹⁰ at the 8, 9and 14 positions respectively are in the β,β,α configurations.

28. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the β,β,β,α configurations.

29. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the α,α,α,α configurations or, if a doublebond is present at the 4-5 or the 5-6 positions, then R¹⁰ at the 8, 9and 14 positions respectively are in the α,α,α configurations.

30. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the β,α,α,α configurations.

31. The method of any of embodiments 1 through 22 wherein no double bondis present at the 4-5 or the 5-6 positions and R¹⁰ at the 5, 8, 9 and 14positions respectively are in the α,α,α,β, α,α,β,α, α,α,β,β, β,α,α,β,β,α,β,α, α,β,β,β, β,α,β,β, or β,β,β,β configurations or, if a doublebond is present at the 4-5 or the 5-6 positions, then R¹⁰ at the 8, 9and 14 positions respectively are in the α,α,β, α,β,α, α,β,β or β,β,βconfigurations.

32. The method of any of embodiments 1 through 31 wherein R¹⁰ at the 5,8, 9 and 14-positions are independently selected from —H, —F, —Cl, —Br,—I, —OH, —OR^(PR), —SH, —NH₂, —COOH, —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂OR^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CHO, —CHS, —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)_(n)—CO₂R^(PR), —CH₂OC(O)—(CH₂)—C(O)SH,—CH₂—C(O)—(CH₂)_(n)—C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)_(n)—NHR^(PR), a monosaccharide, an amino acid, acarbonate, a carbamate, an ester, optionally substituted C1-C20 alkyloptionally selected from —CH₃, —C₂H₅ and —C₃H₇, optionally substitutedC1-C20 ether optionally selected from —OCH₃, —OC₂H₅ and —OC₃H₇,optionally substituted C1-C20 ester optionally selected from acetoxy andpropionoxy, optionally substituted aryl optionally selected from—O-phenyl, —O—-(alkoxy)₁₋₃-phenyl where each alkoxy is optionallyindependently selected (e.g., methoxy or ethoxy) and —O-(halo)₁₋₃-phenylwhere each halogen is optionally independently selected (e.g., —F or—Cl).

33. The method of any of embodiments 1 through 31 wherein R¹⁰ at the 5,8, 9 and 14-positions respectively are

(1) —H, —H, —H, —H;

(2) —H, —H, halogen (—F, —Cl, —Br or —I), —H;

(3) —H, —H, —H, —OH;

(4) —H, —H, halogen (—F, —Cl, —Br or —I), —OH;

(5) -optionally substituted alkyl (e.g., —CH₃, —CH₂OH, —CH₂O-ester,—C₂H₅), —H, —H, —H;

(6) -optionally substituted alkyl (e.g., —CH₃, —CH₂OH, —CH₂O-ester,—C₂H₅), —H, halogen (—F, —Cl, —Br or —I), —H;

(7) -optionally substituted alkyl (e.g., —CH₃, —CH₂OH, —CH₂O-ester,—C₂H₅), —H, —H, —OH;

(8) -acyl (e.g., —C(O)—(CH₂)₀₋₂—CH₃), —H, —H, —H;

(9) -ester (e.g., acetoxy or propionoxy), —H, —H, —H;

(10) -ether (e.g., —O—(CH₂)₀₋₂—CH₃), —H, —H, —H;

(11) -ester (e.g., acetoxy, propionoxy, —O—C(O)—(CH₂)₁₋₆—H), —H, halogen(e.g., —F, —Cl, —Br), —H;

(12) -ester (e.g., acetoxy or propionoxy), —H, —H, —OH;

(13) —H, —H, —H, -acyl (e.g., —C(O)—(CH₂)₀₋₂—CH₃);

(14) —H, —H, —H, -ester (e.g., acetoxy or propionoxy); or

(15) —H, —H, —H, -ether (e.g., —O—(CH₂)₀₋₂—CH₃, —OCH₃, —OC₂H₅, —OCH₂OH,—OCH₂F, —OCH₂Br, —OCH₂COOH, —OCH₂NH₂, —OCH₂CH₂OH, —OCH₂CH₂F, —OCH₂CH₂Br,—OCH₂CH₂COOH or —OCH₂CH₂NH₂).

34. The method of any of embodiments 1 through 33 wherein R¹⁰ at the5-position is in the α-configuration and is optionally selected from —H,—F, —Cl, —Br, —I, —OH, —OR^(PR), —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂OR^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CH(O), —CH(S), —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)_(n)—CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)_(n)—C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)_(n)—NHR^(PR), a monosaccharide, an amino acid, acarbonate, a carbamate and an ester.

35. The method of any of embodiments 1 through 33 wherein R¹⁰ at the5-position is in the β-configuration and is optionally selected from —H,—F, —Cl, —Br, —I, —OH, —OR^(PR), —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂R^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CHO, —CHS, —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)_(n)—CO₂R^(PR), CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)_(n)—C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)_(n)—NHR^(PR), a monosaccharide, an amino acid, acarbonate, a carbamate and an ester.

36. The method of any of embodiments 1 through 35 wherein R¹⁰ at the8-position is in the α-configuration and is optionally selected from —H,—F, —Cl, —Br, —I, —OH, —OR^(PR), —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂OR^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CHO, —CHS, —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)_(n)—CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)_(n)—C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)_(n)—NHR^(PR), a monosaccharide, an amino acid, acarbonate, a carbamate and an ester.

37. The method of any of embodiments 1 through 35 wherein R¹⁰ at the8-position is in the β-configuration and is optionally selected from —H,—F, —Cl, —Br, —I, —OH, —OR^(PR), —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂R^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CHO, —CHS, —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)_(n)—CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)_(n)—C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)_(n)—NHR^(PR), a monosaccharide, an amino acid, acarbonate, a carbamate and an ester.

38. The method of any of embodiments 1 through 37 wherein R¹⁰ at the9-position is in the α-configuration and is optionally selected from —H,—F, —Cl, —Br, —I, —OH, —OR^(PR), —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂OR^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CHO, —CHS, —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)_(n)—CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)_(n)—C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)_(n)—NHR^(PR), a monosaccharide, an amino acid, acarbonate, a carbamate and an ester.

39. The method of any of embodiments 1 through 37 wherein R¹⁰ at the9-position is in the β-configuration and is optionally selected from —H,—F, —Cl, —Br, —I, —OH, —OR^(PR), —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂OR^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CHO, —CHS, —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)_(n)—CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)_(n)—C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)_(n)—NHR^(PR), a monosaccharide, an amino acid, acarbonate, a carbamate and an ester.

40. The method of any of embodiments 1 through 39 wherein R¹⁰ at the14-position is in the α-configuration and is optionally selected from—H, —F, —Cl, —Br, —I, —OH, —OR^(PR), —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂OR^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CHO, —CHS, —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)_(n)—CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)_(n)—C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)_(n)—NHR^(PR), a monosaccharide, an amino acid, acarbonate, a carbamate and an ester.

41. The method of any of embodiments 1 through 39 wherein R¹⁰ at the14-position is in the β-configuration and is optionally selected from—H, —F, —Cl, —Br, —I, —OH, —OR^(PR), —CH₃, —C₂H₅, —C(CH₃)₃, —CH₂OH,—CH₂OR^(PR), —CH₂F, —CH₂Cl, —CH₂Br, —CH₂I, —CHO, —CHS, —CH₂SH,—CH₂SR^(PR), —CH₂NH₂, —CH₂NHR^(PR), —CF₃, —CH₂CH₃, —CH₂CH₂F, —CH₂CF₃,—CH₂OC(O)—(CH₂)_(n)—CH₃, —CH₂OC(O)—(CH₂)_(n)—CO₂H,—CH₂OC(O)—(CH₂)_(n)—CO₂R^(PR), —CH₂OC(O)—(CH₂)_(n)—C(O)SH,—CH₂OC(O)—(CH₂)_(n)—C(O)SR^(PR), —CH₂OC(O)—(CH₂)_(n)—NH₂,—CH₂OC(O)—(CH₂)_(n)—NHR^(PR), a monosaccharide, an amino acid, acarbonate, a carbamate and an ester.

42. The method of any of embodiments 1 through 41 wherein R⁷ is —CH₂—,—CHOH—, —CH(αR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or —CH(halogen)- where thehydroxyl, ester or alkoxy group or the halogen atom is present in theα-configuration and the alkoxy group is optionally selected from —OCH₃,—OC₂H₅ and —OC₃H₇ and the halogen atom is —F, —Cl, —Br or —I.

43. The method of any of embodiments 1 through 41 wherein R⁷ is (i)—CHOH—, —CF₂—, —C(R¹⁰)₂—, —CH(βR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or—CH(halogen)- where the hydroxyl, ester or alkoxy group or the halogenatom is present in the β-configuration and the alkoxy group isoptionally selected from —OCH₃, —OC₂H₅ and —OC₃H₇ and the halogen atomis —F, —Cl, —Br or —I or (ii) wherein R⁷ is —C(βCH₃)(αOH)—,—C(αCH₃)(βOH)—, —C(βCH₃)(αF)—, —C(αCH₃)(βF)—, —CF₂—, —C(βCH₃)(αCl)—,—C(αCH₃)(βCl)—, —CCl₂—, —C(βCH₃)(αBr)—, —C(αCH₃)(βBr)—, —CBr₂—,—C(βCH₃)(αI)—, —C(αCH₃)(βI)—, or —CI₂—.

44. The method of any of embodiments 1 through 41 wherein R⁷ is —C(O)—,—C(═CHCH₃)—, —C(═CH₂)—, —C(═CH—(CH₂)_(n)—CH₃)—,—C(═CH—(CH₂)_(n)—CH₂OH)—, —C(═CH—(CH₂)_(n)—CH₂F)—,—C(═CH—(CH₂)_(n)—CH₂Cl)—, —C(═CH—(CH₂)_(n)—CH₂Br)—,—C(═CH—(CH₂)_(n)—CH₂I)—, —C(═NOH)—, —C(═NO—(CH₂)_(n)—CH₃), wherein n is0, 1, 2, 3 or 4.

45. The method of any of embodiments 1 through 44 wherein R³ is —CH₂—,—CHOH—, —CH(αR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or —CH(halogen)- where thehydroxyl, ester or alkoxy group or the halogen atom is present in theα-configuration and the alkoxy group is optionally selected from —OCH₃,—OC₂H₅ and —OC₃H₇ and the halogen atom is —F, —Cl, —Br or —I.

46. The method of any of embodiments 1 through 44 wherein R⁸ is (i)—CHOH—, —CF₂—, —C(R¹⁰)₂—, —CH(βR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or—CH(halogen)- where the hydroxyl, ester or alkoxy group or the halogenatom is present in the β-configuration and the alkoxy group isoptionally selected from —OCH₃, —OC₂H₅ and —OC₃H₇ and the halogen atomis —F, —Cl, —Br or —I or (ii) wherein R³—C(βCH₃)(αOH)—, —C(αCH₃)(βOH)—,—C(βCH₃)(αF)—, —C(αCH₃)(OF)—, —CF₂—, —C(βCH₃)(αCl)—, —C(αCH₃)(αCl)—,—CCl₂—, —C(βCH₃)(αBr)—, —C(αCH₃)(βBr)—, —CBr₂—, —C(βCH₃)(αI)—,—C(αCH₃)(βI)—, or —Cl₂—.

47. The method of any of embodiments 1 through 44 wherein R⁸ is —C(O)—,—CH₂—, —C(═CHCH₃)—, —C(═CH₂)—, —C(═CH—(CH₂)_(n)—CH₃)—,—C(═CH—(CH₂)_(n)—CH₂OH)—, —C(═CH—(CH₂)_(n)—CH₂F)—,—C(═CH—(CH₂)_(n)—CH₂Cl)—, —C(═CH—(CH₂)_(n)—CH₂Br)—,—C(═CH—(CH₂)_(n)—CH₂I)—, —C(═NOH)—, —C(═NO—(CH₂)_(n)—CH₃), wherein n is0, 1, 2, 3 or 4.

48. The method of any of embodiments 1 through 47 wherein R⁹ is —CH₂—,—CHOH—, —CH(αR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or —CH(halogen)- where thehydroxyl, ester or alkoxy group or the halogen atom is present in theα-configuration and the alkoxy group is optionally selected from —OCH₃,—OC₂H₅ and —OC₃H₇ and the halogen atom is —F, —Cl, —Br or —I.

49. The method of any of embodiments 1 through 47 wherein R⁹ is (i)—CHOH—, —CF₂—, —C(R¹⁰)₂—, —CH(βR¹⁰)—, —CH(ester)-, —CH(alkoxy)- or—CH(halogen)- where the hydroxy, ester or alkoxy group or the halogenatom is present in the β-configuration and the alkoxy group isoptionally selected from —OCH₃, —OC₂H₅ and —OC₃H₇ and the halogen atomis —F, —Cl, —Br or —I, or (ii) wherein R⁹ is —C(βCH₃)(αOH)—,—C(αCH₃)(βOH)—, —C(βCH₃)(αF)—, —C(αCH₃)(OF)—, —CF₂—, —C(βCH₃)(αCl)—,—C(αCH₃)(βCl)—, —CCl₂—, —C(βCH₃)(αBr)—, —C(αCH₃)(βBr)—, —CBr₂—,—C(βCH₃)(αI)—, —C(αCH₃)(βI)—, or —Cl₂—.

50. The method of any of embodiments 1 through 47 wherein R⁹ is —C(O)—,—CH₂—, —C(═CHCH₃)—, —C(═CH₂)—, —C(═CH—(CH₂)_(n)—CH₃)—,—C(═CH—(CH₂)_(n)—CH₂OH)—, —C(═CH—(CH₂)_(n)—CH₂F)—,—C(═CH—(CH₂)_(n)—CH₂Cl)—, —C(═CH—(CH₂)_(n)—CH₂Br)—,—C(═CH—(CH₂)_(n)—CH₂I)—, —C(═NOH)—, —C(═NO—(CH₂)_(n)—CH₃), wherein n is0, 1, 2, 3 or 4.

51. The method of any of embodiments 1 through 50 wherein the subjecthas, or is subject or susceptible to developing, neutropenia.

52. The method of any of embodiments 1-50 wherein the subject is amammal.

53. The method of embodiment 52 wherein the mammal is a human.

54. The method of any preceeding embodiment wherein R⁷ is —CH₂—,—C(α-OH, β-H)—, —C(β-OH, α-H)— or —C(O)—.

55. The method of any preceeding embodiment wherein R³ is —CH₂—,—C(α-OH, β-H)—, —C(β-OH, α-H)—, —C(α-OH, β-F)—, —C(β-OH, α-F)—, —C(α-F,β-H)—, —C(β-F, α-H)— or —C(O)—.

56. The method of any preceeding embodiment wherein R⁹ is —CH₂—,—C(α-OH, —H)—, —C(β-OH, α-H)— or —C(O)—.

57. The method of any preceeding embodiment wherein R^(10A) is —H, α-OH,β-OH or ═O.

58. The method of any preceeding embodiment wherein R^(10B) is —H, β-OH,β-OH or ═O.

59. The method of any preceeding embodiment wherein R^(10C) is —H, α-OH,β-OH or ═O.

60. The method of any preceeding embodiment wherein R^(10D) is —H, α-OH,β-OH or ═O.

61. The method of any preceeding embodiment wherein R^(10E) is —H, α-OH,β-OH or ═O.

62. The method of any preceeding embodiment wherein R¹⁴ are (α-OH, β-H),(β-OH, α-H), (α-C(O)CH₃, β-H), (β-C(O)CH₃, α-H), (α-OH, β-F), (β-OH,α-F), (α-H, β-F), (β-H, α-F), (α-NH₂, β-H), (β-NH₂, (α-H), ═O, ═CH₂ or═CH—CH₃.

63. The method of any preceeding embodiment wherein R¹ are (H, H),(α-OH, β-H), (β-OH, α-H) or ═O.

64. The method of any preceeding embodiment wherein R² are (H, H),(α-OH, β-H), (β-OH, α-H) or ═O.

65. The method of any preceeding embodiment wherein R³ are (H, H),(α-OH, β-H), (β-OH, α-H), (α-H, β-F), (β-H, α-F) or ═O.

66. The method of any of embodiments 1-65 wherein the formula 1 compoundis 16α-bromo-3β-hydroxy-5α-androstan-17-one,16α-fluoro-3β-hydroxy-5α-androstan-17-one,16α-chloro-3β-hydroxy-5α-androstan-17-one,16β-bromo-3β-hydroxy-5α-androstan-17-one,16β-fluoro-3β-hydroxy-5α-androstan-17-one,16β-chloro-3β-hydroxy-5α-androstan-17-one,16α,3β-dihydroxy-5α-androstan-17-one,16β,3β-dihydroxy-5α-androstan-17-one,16α,3α-dihydroxy-5α-androstan-17-one,16β,3α-dihydroxy-5α-androstan-17-one,16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate,3α-hydroxy-16α-fluoroandrostane-17-one,3β-hydroxy-16α-fluoroandrostane-17-one,17α-hydroxy-16α-fluoroandrostane-3-one,17β-hydroxy-16α-fluoroandrostane-3-one,17α-hydroxy-16α-fluoroandrostane-4-one,17β-hydroxy-16α-fluoroandrostane-4-one,17α-hydroxy-16α-fluoroandrostane-6-one,17β-hydroxy-16α-fluoroandrostane-6-one,17α-hydroxy-16α-fluoroandrostane-7-one,17β-hydroxy-16α-fluoroandrostane-7-one,17α-hydroxy-16α-fluoroandrostane-11-one,17β-hydroxy-16α-fluoroandrostane-11-one, 16α-fluoroandrost-5-ene-17-one,7α-hydroxy-16α-fluoroandrost-5-ene-17-one,7β-hydroxy-16α-fluoroandrost-5-ene-17-one,4α-hydroxy-16α-fluoroandrost-5-ene-17-one,3α-hydroxy-16α-fluoroandrost-5-ene-17-one,3β-hydroxy-16α-fluoroandrost-5-ene-17-one,4β-hydroxy-16α-fluoroandrost-5-ene-17-one,6α-hydroxy-16β-fluoroandrost-5-ene-17-one,6β-hydroxy-16α-fluoroandrost-5-ene-17-one,11α-hydroxy-16α-fluoroandrost-5-ene-17-one,11β-hydroxy-16α-fluoroandrost-5-ene-17-one,4α,17β-dihydroxy-16α-fluoroandrost-5-ene,4β,17β-dihydroxy-16α-fluoroandrost-5-ene,6α,17β-dihydroxy-16α-fluoroandrost-5-ene,6β,17β-dihydroxy-16α-fluoroandrost-5-ene,11α,17β-dihydroxy-16α-fluoroandrost-5-ene,11β,17β-dihydroxy-16α-fluoroandrost-5-ene,4α,17α-dihydroxy-16α-fluoroandrost-5-ene,4β,17α-dihydroxy-16α-fluoroandrost-5-ene,6α,17α-dihydroxy-16α-fluoroandrost-5-ene,6β,17α-dihydroxy-16α-fluoroandrost-5-ene,11α,17α-dihydroxy-16α-fluoroandrost-5-ene,11β,17α-dihydroxy-16α-fluoroandrost-5-ene,7α,17β-dihydroxy-16α-fluoroandrost-5-ene,7β,17β-dihydroxy-16α-fluoroandrost-5-ene,3α,17β-dihydroxy-16α-fluoroandrost-5-ene,3β,17β-dihydroxy-16α-fluoroandrost-5-ene,3α,17α-dihydroxy-16α-fluoroandrost-5-ene,3β,17α-dihydroxy-16α-fluoroandrost-5-ene,1α,17β-dihydroxy-16α-fluoroandrost-5-ene,1β,17β-dihydroxy-16α-fluoroandrost-5-ene,2α,17β-dihydroxy-16α-fluoroandrost-5-ene,2β,17β-dihydroxy-16α-fluoroandrost-5-ene,12α,17β-dihydroxy-16α-fluoroandrost-5-ene,12β,17β-dihydroxy-16α-fluoroandrost-5-ene,1α,17α-dihydroxy-16α-fluoroandrost-5-ene,1β,17α-dihydroxy-16α-fluoroandrost-5-ene,2α,17α-dihydroxy-16α-fluoroandrost-5-ene,2β,17α-dihydroxy-16α-fluoroandrost-5-ene,12α,17α-dihydroxy-16α-fluoroandrost-5-ene,12β,17α-dihydroxy-16α-fluoroandrost-5-ene,15α,17β-dihydroxy-16α-fluoroandrost-5-ene,15β,17β-dihydroxy-16α-fluoroandrost-5-ene,17β,18-dihydroxy-16α-fluoroandrost-5-ene,17β,19-dihydroxy-16α-fluoroandrost-5-ene,15α,17β-dihydroxy-16α-fluoroandrost-5-ene,15β,17α-dihydroxy-16α-fluoroandrost-5-ene,17α,18-dihydroxy-16α-fluoroandrost-5-ene,17α,19-dihydroxy-16α-fluoroandrost-5-ene,16α-fluoroandrost-4-ene-17-one,7α-hydroxy-16α-fluoroandrost-4-ene-17-one,7β-hydroxy-16α-fluoroandrost-4-ene-17-one,3α-hydroxy-16α-fluoroandrost-4-ene-17-one,3β-hydroxy-16α-fluoroandrost-4-ene-17-one,4α-hydroxy-16α-fluoroandrost-4-ene-17-one,4β-hydroxy-16α-fluoroandrost-4-ene-17-one,6α-hydroxy-16β-fluoroandrost-4-ene-17-one,6β-hydroxy-16α-fluoroandrost-4-ene-17-one,11α-hydroxy-16β-fluoroandrost-4-ene-17-one,11β-hydroxy-16α-fluoroandrost-4-ene-17-one,4α,17β-dihydroxy-16α-fluoroandrost-4-ene,4β,17β-dihydroxy-16α-fluoroandrost-4-ene,6α,17β-dihydroxy-16α-fluoroandrost-4-ene,6β,17β-dihydroxy-16α-fluoroandrost-4-ene,11α,17β-dihydroxy-16α-fluoroandrost-4-ene,11β,17β-dihydroxy-16α-fluoroandrost-4-ene,4α,17-dihydroxy-16α-fluoroandrost-4-ene,4β,17α-dihydroxy-16α-fluoroandrost-4-ene,6α,17α-dihydroxy-16α-fluoroandrost-4-ene,6β,17α-dihydroxy-16α-fluoroandrost-4-ene,11α,17α-dihydroxy-16α-fluoroandrost-4-ene,11β,17α-dihydroxy-16α-fluoroandrost-4-ene,7α,17β-dihydroxy-16α-fluoroandrost-4-ene,7β,17β-dihydroxy-16α-fluoroandrost-4-ene,3α,17β-dihydroxy-16α-fluoroandrost-4-ene,3β,17β-dihydroxy-16α-fluoroandrost-4-ene,3α,17α-dihydroxy-16α-fluoroandrost-4-ene,3β,17α-dihydroxy-16α-fluoroandrost-4-ene,1α,17β-dihydroxy-16α-fluoroandrost-4-ene,1β,17β-dihydroxy-16α-fluoroandrost-4-ene,2α,17β-dihydroxy-16α-fluoroandrost-4-ene,2β,17β-dihydroxy-16α-fluoroandrost-4-ene,12α,17β-dihydroxy-16α-fluoroandrost-4-ene,12β,17β-dihydroxy-16α-fluoroandrost-4-ene,1α,17α-dihydroxy-16α-fluoroandrost-4-ene,1β,17α-dihydroxy-16α-fluoroandrost-4-ene,2α,17α-dihydroxy-16α-fluoroandrost-4-ene,2β,17α-dihydroxy-16α-fluoroandrost-4-ene,12α,17α-dihydroxy-16α-fluoroandrost-4-ene,12β,17α-dihydroxy-16α-fluoroandrost-4-ene,15α,17β-dihydroxy-16α-fluoroandrost-4-ene,15β,17β-dihydroxy-16α-fluoroandrost-4-ene,17β,18-dihydroxy-16α-fluoroandrost-4-ene,17β,19-dihydroxy-16α-fluoroandrost-4-ene,15α,17α-dihydroxy-16α-fluoroandrost-4-ene,15β,17α-dihydroxy-16α-fluoroandrost-4-ene,17α,18-dihydroxy-16α-fluoroandrost-4-ene,17α,19-dihydroxy-16α-fluoroandrost-4-ene, 3β,17β-dihydroxyandrost-5-ene,3β-hydroxy-7,17-dioxoandrost-5-ene, 3α-hydroxy-7,17-dioxoandrost-5-ene,3β,17-dioxoandrost-5-ene, 3β,17-dioxoandrost-4-ene,3β,17-dioxoandrost-1,4-diene, 3β,7β,17β-trihydroxyandrost-5-ene,3β,7β,17β-trihydroxyandrostane, 3β,16α-dihydroxy-17-oxoandrostane,3α,16α-dihydroxy-17-oxoandrostane, 3β,16β-dihydroxy-17-oxoandrostane,3α,16β-dihydroxy-17-oxoandrostane, 3β,16α,17β-trihydroxyandrostane,3β,16β,17β-trihydroxyandrostane, 3β,16α,17α-trihydroxyandrostane,3β,16β,17α-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane,3α,16β,17β-trihydroxyandrostane or an analog of any of the foregoingcompounds that is suitably substituted to fall within the scope of theembodiment, e.g., wherein an R¹⁰ is a hydroxyl, thiol, optionallysubstituted alkyl or a halogen such as fluorine or bromine at the 1-,2-, 4-, 6-, 7-, 9-11-, 12-, 14-, 15- or 16-position, wherein the R¹⁰ ispresent in the α-configuration or the β-configuration.

67. A method to treat, ameliorate or slow the progression of cysticfibrosis in a human comprising administering to the human an effectiveamount of a formula 1 compound of any preceeding embodiment.

68. The method of embodiment 67, wherein one or more symptoms orsyndromes are ameliorated, or wherein the progression of the disease isreduced.

69. The method of embodiment 68, wherein the one or more symptoms orsyndromes are 1, 2, 3 or more of Staphylococcus (e.g., S. aureus),Haemophilus influenzae, Pseudomonas or Burkholderia respiratory tract orlung infection or propensity to develop a detectable infection orcolonization, coughing, wheezing, cyanosis, bronchiolitis, bronchospasm,pneumothorax, hemoptysis, pancreatic exocrine insufficiency,bronchiectatic lung disease, atelectasis-consolidation, pulmonary edema,increased lung vascular hydrostatic pressure, increased lung vascularpermeability, sinusitis, respiratory insufficiency, bronchial wall orinterlobular septa thickening, reduction of forced expiratory volume in1 second, dyspnea, impaired male fertility, elevated sweat chloride,mucous plugging, tree-in-bud sign, mosaic perfusion pattern, glucoseintolerance or abnormal elevation of one or more of IL-4, IL-8, RANTES,neutrophil elastase, eosinophils, macrophages, neutrophils, eosinophilcationic protein or cysteinyl leukotrienes.

70. The method of embodiment 67, 68 or 69 wherein the method furthercomprises another suitable CF treatment, which is optionally selectedfrom oral or aerosol corticosteroid treatment, ibuprofen treatment,DNAse treatment, IL-10 treatment, diet control, vaccination againstpathogens, or chest physical therapy.

71. The method of embodiment 67, 68, 69 or 70 wherein the F1C is16α-bromoepiandrosterone, 16α-bromoepiandrosterone hemihydrate,16α-hydroxyepiandrosterone, 16β-hydroxyepiandrosterone,3α,17β-dihydroxyandrostane, 3β,17β-dihydroxyandrostane,3α,16α,17β-trihydroxyandrostane, 3α,16β,17β-trihydroxyandrostane,3β,16α,17β-trihydroxyandrostane, 3β,16β,17β-trihydroxyandrostane, or anester, carbonate or other analog of any of these compounds that canconvert to the compound by metabolism or hydrolysis.

72. A method to prevent, treat or ameliorate neutropenia in a humancomprising administering to the human an effective amount of a formula 1compound of any of embodiments 1-66, wherein the neutropenia ispostinfectious neutropenia, autoimmune neutropenia, chronic idiopathicneutropenia or a neutropenia resulting from or potentially resultingresult from a cancer chemotherapy, chemotherapy for an autoimmunedisease, an antiviral therapy, radiation exposure, tissue or solid organallograft or xenograft rejection or immune suppression therapy in tissueor solid organ transplantation or aging or immunesenescence.

73. The method of embodiment 72 wherein one R⁴ is in the β-configurationor the α-configuration and is —NH₂, a substituted amine or an amide,which is optionally selected from —NH₂, —NHCH₃, —N(CH₃)₂, —NHR^(PR),—NH—C(O)—H and —NH—C(O)-optionally substituted alkyl, e.g.,—NH—C(O)—CH₃.

74. The method of embodiment 73 wherein the other R⁴ is —H, optionallysubstituted alkyl, —CN, —SCN or —OH.

75. The method of embodiment 72 wherein the F1C is3β-hydroxy-17β-aminoandrost-5-ene,3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-16β-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-16,16-difluoro-17β-aminoandrost-5-ene,3β,16α-dihydroxy-17β-aminoandrost-5-ene,3β,16β-dihydroxy-17β-aminoandrost-5-ene,3β-hydroxy-16,16-dimethyl-17β-aminoandrost-5-ene, an ester or carbonateof any of these compounds or an analog of any of the foregoing compoundswhere the double bond at the 5-6 position is absent and a hydrogen orother R¹⁰ moiety is present at the 5-position in the α- orβ-configuration and/or wherein the hydroxyl group (or ester or carbonateanalog) at the 3-position is present in the α-configuration.

76. A compound of formula 1 as defined in embodiment 1.

77. The compound of embodiment 76 wherein one R³ is a halogen, the otherR³ is not a halogen and one R⁴ is —NH₂, a substituted amine, an N-linkedamino acid, —N(R^(PR))₂ or an amide, where R^(PR) independently ortogether are —H or a protecting group.

78. The compound of embodiment 77 wherein one R⁴ is —NH₂.

79. The compound of embodiment 77 wherein the compound is3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-16β-fluoro-17β-aminoandrost-5-ene,3α-hydroxy-16α-fluoro-17β-aminoandrost-5-ene,3α-hydroxy-16β-fluoro-17β-aminoandrost-5-ene,3β-hydroxy-16α-fluoro-17β-aminoandrost-4-ene,3β-hydroxy-16β-fluoro-17β-aminoandrost-4-ene,3α-hydroxy-16α-fluoro-17β-aminoandrost-4-ene,3α-hydroxy-16β-fluoro-17β-aminoandrost-4-ene,3β-hydroxy-16α-fluoro-17β-aminoandrostane,3β-hydroxy-16β-fluoro-17β-aminoandrostane,3α-hydroxy-16β-fluoro-17β-aminoandrostane,3α-hydroxy-16β-fluoro-17β-aminoandrostane,3β-hydroxy-16α-fluoro-17β-amino-5β-androstane,3β-hydroxy-16β-fluoro-17β-amino-5β-androstane,3α-hydroxy-16α-fluoro-17β-amino-5β-androstane,3α-hydroxy-16β-fluoro-17β-amino-5β-androstane or an analog of any ofthese compounds wherein (1) the compound is substituted with an R¹⁰moiety other than —H at the 1, 2, 4, 6, 7, 11, 12, 14 or 15 positionand/or (2) the compound is substituted at one or two of the 2, 11 or 15positions with an independently selected —O—, —S— or —NH— moiety thatreplaces the one or two —CH₂— moieties.

80. A composition comprising a compound of formula 1 as defined in anypreceding embodiment and one, two, three, four, five or more excipients.

81. A method to treat or to reduce the severity of a chronic allergy oran atopic disease, or one or more symptoms of the chronic allergy oratopic disease in a subject in need thereof, comprising administering aneffective amount of a formula 1 compound of embodiment 1, wherein

one R¹ is, or both R¹ together are, —OH, —OR^(PR), —SR^(PR),—O—Si—(R¹³)₃, —COOH, —OSO₃H, —OPO₃H, ═O, ═S, an ester, a thioester, athionoester, a phosphoester, a phosphothioester, a phosphonoester, aphosphiniester, a sulfite ester, a sulfate ester, an amide, an aminoacid, a peptide, an ether, a thioether, a carbonate or a carbamate, andthe other R¹ is independently chosen; and

one R⁴ is, or both R⁴ together are, —OH, —OR^(PR), —SR^(PR),—N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN, —NO₂, —NH₂, —COOH,—OSO₃H, —OPO₃H, ═O, ═S, ═N—OH, ═N—O-optionally substituted alkyl, anester, a thioester, a thionoester, a phosphoester, a phosphothioester, aphosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, anamide, an amino acid, a peptide, an ether, a thioether, an acyl group, athioacyl group, a carbonate or a carbamate, and the other R⁴ isindependently chosen.

82. The method of embodiment 81 wherein the compound is16α-bromoepiandrosterone, 16α-bromoepiandrosterone hemihydrate,16α-iodoepiandrosterone, 16-oxoepiandrosterone, 16-oxoandrosterone,3β,16α-dihydroxyandrostane-17-one, 3α,16α-dihydroxyandrostane-17-one,3β,16β-dihydroxyandrostane-17-one, 3α,16β-dihydroxyandrostane-17-one,3β,16α,17β-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane,3β,16β,17β-trihydroxyandrostane, 3α,16β,17β-trihydroxyandrostane, or ananalog of any of these compounds that is (1) 2-oxa or 11-oxasubstituted, (2) substituted at the 7-position with an α-halogen,β-halogen, α-hydroxyl, β-hydroxyl or oxo moiety, (3) a D-ring homoanalog, (4) a 19-nor analog and/or (5) an analog of any of the foregoingcompounds that is substituted with an R¹⁰ substituent disclosed herein,e.g., wherein the R¹⁰ is a hydroxyl, thiol, optionally substituted alkylor a halogen such as fluorine or bromine at the 1-, 2-, 4-, 6-, 9-11-,12-, 14-, 15- or 16-positions, wherein the R¹⁰, e.g., the hydroxyl,thiol, optionally substituted alkyl or halogen is present in theα-configuration or the β-configuration.

83. The method of embodiment 81 or 82 wherein the level or activity ofIgE in the subject is at least transiently detectably reduced, e.g.,shortly after allergen exposure (such as within about 1 hour to about 1week) or at one more later times.

84. A method to increase the efficacy of an immune response to dendriticcells in a subject, comprising (1) contacting for a sufficient time aneffective amount of a formula 1 compound of any of embodiments 1-66 andan effective amount of a non-self antigen with the subject's dendriticcells in vitro, (2) optionally expanding the dendritic cells in vitro inthe presence or absence of the formula 1 compound and/or the antigen,(3) infusing the dendritic cells into the subject, (4) optionallyadministering an effective amount of the formula 1 compound to thesubject and/or optionally administering an effective amount of thenon-self antigen to the subject.

85. The method of embodiment 84 wherein the non-self antigen comprisesan antigen derived or obtained from an infectious agent or from amalignant cell or a pre-malignant cell, wherein the malignant orpre-malignant cell is from the subject or is from another individual ofthe same species as the subject.

86. The method of embodiment 84 or 85 wherein one R¹ is, or both R¹together are, —H, —OH, —OR^(PR), —SR^(PR), —O—Si—(R¹³)₃, —COOH, —OSO₃H,—OPO₃H, ═O, ═S, an ester, a thioester, a thionoester, a phosphoester, aphosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, asulfate ester, an amide, an amino acid, a peptide, an ether, athioether, a carbonate or a carbamate, and the other R¹ is independentlychosen; and

one R⁴ is, or both R⁴ together are, —OH, —OR^(PR), —SR^(PR),—N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN, —NO₂, —NH₂, —COOH,—OSO₃H, —OPO₃H, ═O, ═S, ═N—OH, ═N—O-optionally substituted alkyl, anester, a thioester, a thionoester, a phosphoester, a phosphothioester, aphosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, anamide, an amino acid, a peptide, an ether, a thioether, an acyl group, athioacyl group, a carbonate or a carbamate, and the other R⁴ isindependently chosen.

87. The method of embodiment 86 wherein the compound is3β,17β-dihydroxyandrost-5-ene, 3β,7β,17β-trihydroxyandrost-5-ene,3β,17β-dihydroxyandrost-1,5-diene,3β,7β,17β-trihydroxyandrost-1,5-diene,3β,17β-dihydroxy-16-haloandrost-5-ene,3β,7β,17β-trihydroxy-16-haloandrost-5-ene,16α-fluoro-17-oxoandrost-5-ene,3α-hydroxy-16α-fluoro-17-oxoandrost-5-ene,3β-hydroxy-16α-fluoro-17-oxoandrost-5-ene,3β,17β-dihydroxy-16α-fluoroandrost-5-ene,3α,17β-dihydroxy-16α-fluoroandrost-5-ene, 16α-bromoepiandrosterone,16α-bromoepiandrosterone hemihydrate, 16α-iodoepiandrosterone,16-oxoepiandrosterone, 16-oxoandrosterone,3β,16α-dihydroxyandrostane-17-one, 3α,16α-dihydroxyandrostane-17-one,3β,16β-dihydroxyandrostane-17-one, 3α,16β-dihydroxyandrostane-17-one,3β,16α,17β-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane,3β,16β,17β-trihydroxyandrostane, 3α,16β,17β-trihydroxyandrostane, or ananalog of any of these compounds that is (1) 11-oxa substituted or 2-oxasubstituted if no double bond is present at the 1-2 position, (2)substituted at the 7-position with an α-halogen, β-halogen, α-hydroxyl,β-hydroxyl or oxo moiety (3), (3) a D-ring homo analog, (4) a 19-noranalog and/or (5) an analog of any of the foregoing compounds that issubstituted with an R¹⁰ substituent disclosed herein, e.g., wherein theR¹⁰ is a hydroxyl, thiol, optionally substituted alkyl or a halogen suchas fluorine or bromine at the 1-, 2-, 4-, 6-, 9-11-, 12-, 14-, 15- or16-positions, wherein the R¹⁰, e.g., the hydroxyl, thiol, optionallysubstituted alkyl or halogen is present in the α-configuration or theβ-configuration.

88. A method to increase the efficacy of allergy vaccinations in asubject having an allergy, comprising (1) at an effective time before orduring vaccination of the subject with an allergen, administering to thesubject an effective amount of a formula 1 compound of embodiment 1, (2)optionally administering to the subject an effective amount of theformula 1 compound daily or intermittently for 2, 3, 4, 5, 6, 7, 14 ormore days after the vacination of step (1), (3) after passage ofsufficient time, repeating step (1) and (4) after passage of sufficienttime, optionally repeating steps (1), (3) and/or (2).

89. The method of embodiment 88 wherein the subject has a chronicallergy or atopic disease, optionally selected from allergic rhinitis,psoriasis, eczema, gastrointestinal allergies, atopic dermatitisconditions, allergic asthma, food allergies and hay fever and (1)wherein the level of IgE in the subject is at least transientlydetectably reduced during or after exposure to the allergen, or (2)wherein the total number of anti-allergic vaccinations that are neededto reduce allergy reactions or symptoms to allergen exposure is reducedor there is an increase in the quality or length of an effectiveresponse to allergen vaccination or there is an increase the proportionof subjects in which allergy vaccination is effective.

90. The method of embodiment 88 or 89 wherein one R¹ is, or both R¹together are, —H, —OH, —OR^(PR), —SR^(PR), —O—Si—(R¹³)₃, —COOH, —OSO₃H,—OPO₃H, ═O, ═S, an ester, a thioester, a thionoester, a phosphoester, aphosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, asulfate ester, an amide, an amino acid, a peptide, an ether, athioether, a carbonate or a carbamate, and the other R¹ is independentlychosen; and

one R⁴ is, or both R⁴ together are, —OH, —OR^(PR), —SR^(PR),—N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN, —NO₂, —NH₂, —COOH,—OSO₃H, —OPO₃H, ═O, ═S, ═N—OH, ═N—O-optionally substituted alkyl, anester, a thioester, a thionoester, a phosphoester, a phosphothioester, aphosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, anamide, an amino acid, a peptide, an ether, a thioether, an acyl group, athioacyl group, a carbonate or a carbamate, and the other R⁴ isindependently chosen.

91. The method of embodiment 90 wherein the compound is3β,17β-dihydroxyandrost-5-ene, 3β,7β,17β-trihydroxyandrost-5-ene,3β,17β-dihydroxyandrost-1,5-diene,3β,7β,17β-trihydroxyandrost-1,5-diene,3β,17β-dihydroxy-16-haloandrost-5-ene,3β,7β,17β-trihydroxy-16-haloandrost-5-ene,16α-fluoro-17-oxoandrost-5-ene,3α-hydroxy-16α-fluoro-17-oxoandrost-5-ene,3β-hydroxy-16α-fluoro-17-oxoandrost-5-ene,3β,17β-dihydroxy-16α-fluoroandrost-5-ene,3α,17β-dihydroxy-16α-fluoroandrost-5-ene, 16α-bromoepiandrosterone,16α-bromoepiandrosterone hemihydrate, 16α-iodoepiandrosterone,16-oxoepiandrosterone, 16-oxoandrosterone,3β,16α-dihydroxyandrostane-17-one, 3α,16α-dihydroxyandrostane-17-one,3β,16β-dihydroxyandrostane-17-one, 3α,16β-dihydroxyandrostane-17-one,3β,16α,17β-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane,3β,16β,17β-trihydroxyandrostane, 3α,16β,17β-trihydroxyandrostane, or ananalog of any of these compounds that is (1)₁₋₁-oxa substituted or 2-oxasubstituted if no double bond is present at the 1-2 position, (2)substituted at the 7-position with an α-halogen, β-halogen, α-hydroxyl,β-hydroxyl or oxo moiety, (3) a D-ring homo analog, (4) a 19-nor analogand/or (5) an analog of any of the foregoing compounds that issubstituted with an R¹⁰ substituent disclosed herein, e.g., wherein theR¹⁰ is a hydroxyl, thiol, optionally substituted alkyl or a halogen suchas fluorine or bromine at the 1-, 2-, 4-, 6-, 9-11-, 12-, 14-, 15- or16-positions, wherein the R¹⁰, e.g., the hydroxyl, thiol, optionallysubstituted alkyl or halogen is present in the α-configuration or theβ-configuration.

92. A method to prevent, treat or to reduce the severity of vascular ormicrovascular occlusions in human sickle cell or thalassemia diseases,comprising administering to the patient an effective amount of a formula1 compound of any of embodiments 1-66.

93. The method of embodiment 92 further comprising daily or intermittentadministration of the formula 1 compound.

94. The method of embodiment 92 or 93 further comprising monitoring thesubject's blood cell status to determine if further administration ofthe formula 1 compound is desirable, and, if further treatment isdesirable, administering to the patient an effective amount of theformula 1 compound.

95. The method of embodiment 92, 93 or 94 wherein the frequency ofobserved vascular occlusion events in the subject or the severity of thesubject's symptoms of vascular occlusions is at least transientlydetectably reduced.

96. The method of embodiment 92, 93, 95 or 95 wherein one R¹ is, or bothR¹ together are, —H, —OH, —OR^(PR), —SR^(PR), —O—Si—(R¹³)₃, —COOH,—OSO₃H, —OPO₃H, ═O, ═S, an ester, a thioester, a thionoester, aphosphoester, a phosphothioester, a phosphonoester, a phosphiniester, asulfite ester, a sulfate ester, an amide, an amino acid, a peptide, anether, a thioether, a carbonate or a carbamate, and the other R¹ isindependently chosen; and

one R⁴ is, or both R⁴ together are, —OH, —OR^(PR), —SR^(PR),—N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN, —NO₂, —NH₂, —COOH,—OSO₃H, —OPO₃H, ═O, ═S, ═N—OH, ═N—O-optionally substituted alkyl, anester, a thioester, a thionoester, a phosphoester, a phosphothioester, aphosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, anamide, an amino acid, a peptide, an ether, a thioether, an acyl group, athioacyl group, a carbonate or a carbamate, and the other R⁴ isindependently chosen.

97. The method of embodiment 90 wherein the compound is3β,17β-dihydroxyandrost-5-ene, 3β,7β,17β-trihydroxyandrost-5-ene,3β,17β-dihydroxyandrost-1,5-diene,3β,7β,17β-trihydroxyandrost-1,5-diene,3β,17β-dihydroxy-16-haloandrost-5-ene,3β,7β,17β-trihydroxy-16-haloandrost-5-ene,16α-fluoro-17-oxoandrost-5-ene,3α-hydroxy-16α-fluoro-17-oxoandrost-5-ene,3β-hydroxy-16α-fluoro-17-oxoandrost-5-ene,3β,17β-dihydroxy-16α-fluoroandrost-5-ene,3α,17β-dihydroxy-16α-fluoroandrost-5-ene, 16α-bromoepiandrosterone,16α-bromoepiandrosterone hemihydrate, 16α-iodoepiandrosterone,16-oxoepiandrosterone, 16-oxoandrosterone,3β,16α-dihydroxyandrostane-17-one, 3α,16α-dihydroxyandrostane-17-one,3β,16β-dihydroxyandrostane-17-one, 3α,16β-dihydroxyandrostane-17-one,3β,16α,17β-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane,3β,16β,17β-trihydroxyandrostane, 3α,16β,17β-trihydroxyandrostane, or ananalog of any of these compounds that is (1)₁₋₁-oxa substituted or 2-oxasubstituted if no double bond is present at the 1-2 position, (2)substituted at the 7-position with an α-halogen, β-halogen, α-hydroxyl,β-hydroxyl or oxo moiety, (3) a D-ring homo analog, (4) a 19-nor analogand/or (5) an analog of any of the foregoing compounds that issubstituted with an R¹⁰ substituent disclosed herein, e.g., wherein theR¹⁰ is a hydroxyl, thiol, optionally substituted alkyl or a halogen suchas fluorine or bromine at the 1-, 2-, 4-, 6-, 9-11-, 12-, 14-, 15- or16-positions, wherein the R¹⁰, e.g., the hydroxyl, thiol, optionallysubstituted alkyl or halogen is present in the α-configuration or theβ-configuration.

98. A method to identify a compound that modulates the expression in acell of the level of or an activity of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ormore genes or gene products or gene transcripts in the cell, comprisingcontacting an effective amount of the compound with the cell undersuitable conditions and for a sufficient time to detectably modulate theactivity or level of the genes, or gene products in the cell, whereinthe compound is a compound of any of embodiments 1-65.

99. The method of embodiment 98 wherein the genes or gene products areoptionally selected from the group consisting of the genes or geneproducts disclosed herein.

100. The method of embodiment 98 or 99 wherein the genes or geneproducts are selected from the group consisting of USF1, c-Fos, EGR1,Cul1, RIPK2, IκBα, IκBKb, NF-κB1 p50, FCAR, c-Fos/C/EBPβ, RANTES, ICAM1,TSG (TNFAIP6), IL-2 receptor α, GRO2, GRO3, HO1, Jun B, c-Fos/JunBcomplex, JunB/ATF3 complex, c-Jun, c-Fos/c-Jun complex, ATF-3, MMP1,TSG-6 (TNFAIP3), EGR1, TGFβ, ATF-3/c-Jun complex, c-Fos, MMP3, IL-8,STAT5A, STAT5B, CDKN1A, IFNγ receptor 2 (IFNγR2), T-bet, C reactiveprotein, immunoglobulin E, an AP-1 family protein, SOD2, GATA-3, Jak2,Tyk2, stat1, stat3, stat4, stat5, stat6, MIP-1α, MIP-2, IP-10, MCP-1,TNF-α, TNF-β, LT-β, IFN-α, IFN-β, TGF-β1, NF-κB, IL-1α, IL-1β, IL-4,IL-6, IL-10, IL-12 receptor β1, IL-12p35, IL-12p40, IL-23 and IL-23receptor.

101. The method of embodiment 98, 99 or 100 wherein the level oractivity of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, about 30, about 50, about 100, about 150, about 200, about250, about 300, about 500, about 700 or about 1000 of the genes or geneproducts is detectably modulated at least transiently.

102. The method of any of embodiments 98-101 wherein the level or anactivity of the gene product is a detectable increase in the level ofthe mRNA, the protein or one or more biological activities associatedwith the gene product.

103. The method of embodiment 102 wherein the increase is a transientincrease of about 1 hour to about 12 hours.

104. The method of embodiment 102 wherein the level or an activity ofthe gene product is a detectable decrease in the level of the mRNA, theprotein or one or more biological activities associated with the geneproduct.

105. The method of embodiment 104 wherein the increase is a transientdecrease of about 1 hour to about 12 hours.

106. The method of any of embodiments 98-101 wherein the modulation isan increase or a decrease of at least about 2-fold to about 1000-fold inthe level or an activity of the mRNA, the protein or at least onebiological activity associated with the gene product.

107. The method of any of embodiments 98-106 wherein one R¹ is, or bothR¹ together are, —H, —OH, —OR^(PR), —SR^(PR), —O—Si—(R¹³)₃, —COOH,—OSO₃H, —OPO₃H, ═O, ═S, an ester, a thioester, a thionoester, aphosphoester, a phosphothioester, a phosphonoester, a phosphiniester, asulfite ester, a sulfate ester, an amide, an amino acid, a peptide, anether, a thioether, a carbonate or a carbamate, and the other R¹ isindependently chosen; and

one R⁴ is, or both R⁴ together are, —OH, —OR^(PR), —SR^(PR),—N(R^(PR))₂, —O—Si—(R¹³)₃, —CHO, —CHS, —CN, —SCN, —NO₂, —NH₂, —COOH,—OSO₃H, —OPO₃H, ═O, ═S, ═N—OH, ═N—O-optionally substituted alkyl, anester, a thioester, a thionoester, a phosphoester, a phosphothioester, aphosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, anamide, an amino acid, a peptide, an ether, a thioether, an acyl group, athioacyl group, a carbonate or a carbamate, and the other R⁴ isindependently chosen.

108. The method of any of embodiments 98-106 wherein the formula 1compound is 16α-bromo-3β-hydroxy-5α-androstan-17-one,16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate,16α-fluoro-3β-hydroxy-5α-androstan-17-one,16α-chloro-3β-hydroxy-5α-androstan-17-one,16β-bromo-3β-hydroxy-5α-androstan-17-one,16β-fluoro-3β-hydroxy-5α-androstan-17-one,16β-chloro-3β-hydroxy-5α-androstan-17-one,16α,3β-dihydroxy-5α-androstan-17-one,16β,3β-dihydroxy-5α-androstan-17-one,16α,3α-dihydroxy-5α-androstan-17-one,16β,3α-dihydroxy-5α-androstan-17-one,16α-bromo-3β-hydroxy-5α-androstan-17-one hemihydrate,3α-hydroxy-16α-fluoroandrostane-17-one,3β-hydroxy-16α-fluoroandrostane-17-one,17α-hydroxy-16α-fluoroandrostane-3-one,17β-hydroxy-16α-fluoroandrostane-3-one,17α-hydroxy-16α-fluoroandrostane-4-one,17β-hydroxy-16α-fluoroandrostane-4-one,17α-hydroxy-16α-fluoroandrostane-6-one,17β-hydroxy-16α-fluoroandrostane-6-one,17α-hydroxy-16α-fluoroandrostane-7-one,17β-hydroxy-16α-fluoroandrostane-7-one,17β-hydroxy-16β-fluoroandrostane-11-one,17β-hydroxy-16α-fluoroandrostane-11-one, 16α-fluoroandrost-5-ene-17-one,7α-hydroxy-16α-fluoroandrost-5-ene-17-one,7β-hydroxy-16α-fluoroandrost-5-ene-17-one,4α-hydroxy-16α-fluoroandrost-5-ene-17-one,3α-hydroxy-16α-fluoroandrost-5-ene-17-one,3β-hydroxy-16α-fluoroandrost-5-ene-17-one,4β-hydroxy-16α-fluoroandrost-5-ene-17-one,6α-hydroxy-16α-fluoroandrost-5-ene-17-one,6β-hydroxy-16α-fluoroandrost-5-ene-17-one,11α-hydroxy-16α-fluoroandrost-5-ene-17-one,11β-hydroxy-16α-fluoroandrost-5-ene-17-one,4α,17β-dihydroxy-16α-fluoroandrost-5-ene,4β,17β-dihydroxy-16α-fluoroandrost-5-ene,6α,17β-dihydroxy-16α-fluoroandrost-5-ene,6β,17β-dihydroxy-16α-fluoroandrost-5-ene,11α,17β-dihydroxy-16α-fluoroandrost-5-ene,11β,17β-dihydroxy-16α-fluoroandrost-5-ene,4α,17-dihydroxy-16α-fluoroandrost-5-ene,4β,17α-dihydroxy-16α-fluoroandrost-5-ene,6α,17α-dihydroxy-16α-fluoroandrost-5-ene,6β,17α-dihydroxy-16α-fluoroandrost-5-ene,11α,17α-dihydroxy-16α-fluoroandrost-5-ene,11β,17α-dihydroxy-16α-fluoroandrost-5-ene,7α,17β-dihydroxy-16α-fluoroandrost-5-ene,7β,17β-dihydroxy-16α-fluoroandrost-5-ene,3α,17β-dihydroxy-16α-fluoroandrost-5-ene,3β,17β-dihydroxy-16α-fluoroandrost-5-ene,3α,17α-dihydroxy-16α-fluoroandrost-5-ene,3β,17α-dihydroxy-16α-fluoroandrost-5-ene,1α,17β-dihydroxy-16α-fluoroandrost-5-ene,1β,17β-dihydroxy-16α-fluoroandrost-5-ene,2α,17β-dihydroxy-16α-fluoroandrost-5-ene,2β,17β-dihydroxy-16α-fluoroandrost-5-ene,12α,17β-dihydroxy-16α-fluoroandrost-5-ene,12β,17β-dihydroxy-16α-fluoroandrost-5-ene,1α,17α-dihydroxy-16α-fluoroandrost-5-ene,1β,17α-dihydroxy-16α-fluoroandrost-5-ene,2α,17α-dihydroxy-16β-fluoroandrost-5-ene,2β,17α-dihydroxy-16α-fluoroandrost-5-ene,12α,17β-dihydroxy-16β-fluoroandrost-5-ene,12β,17α-dihydroxy-16α-fluoroandrost-5-ene,15α,17β-dihydroxy-16α-fluoroandrost-5-ene,15β,17β-dihydroxy-16α-fluoroandrost-5-ene,17β,18-dihydroxy-16α-fluoroandrost-5-ene,17β,19-dihydroxy-16α-fluoroandrost-5-ene,15α,17α-dihydroxy-16α-fluoroandrost-5-ene,15β,17α-dihydroxy-16α-fluoroandrost-5-ene,17α,18-dihydroxy-16α-fluoroandrost-5-ene,17α,19-dihydroxy-16α-fluoroandrost-5-ene,16α-fluoroandrost-4-ene-17-one,7α-hydroxy-16α-fluoroandrost-4-ene-17-one,7β-hydroxy-16α-fluoroandrost-4-ene-17-one,3α-hydroxy-16α-fluoroandrost-4-ene-17-one,3β-hydroxy-16α-fluoroandrost-4-ene-17-one,4α-hydroxy-16α-fluoroandrost-4-ene-17-one,4β-hydroxy-16α-fluoroandrost-4-ene-17-one,6α-hydroxy-16α-fluoroandrost-4-ene-17-one,6β-hydroxy-16α-fluoroandrost-4-ene-17-one,11-hydroxy-16α-fluoroandrost-4-ene-17-one,11β-hydroxy-16α-fluoroandrost-4-ene-17-one,4α,17β-dihydroxy-16α-fluoroandrost-4-ene,4β,17β-dihydroxy-16α-fluoroandrost-4-ene,6α,17β-dihydroxy-16α-fluoroandrost-4-ene,6β,17β-dihydroxy-16α-fluoroandrost-4-ene,11α,17β-dihydroxy-16α-fluoroandrost-4-ene,11β,17β-dihydroxy-16α-fluoroandrost-4-ene,4α,17α-dihydroxy-16β-fluoroandrost-4-ene,4β,17α-dihydroxy-16α-fluoroandrost-4-ene,6α,17α-dihydroxy-16β-fluoroandrost-4-ene,6β,17α-dihydroxy-16α-fluoroandrost-4-ene,11α,17-dihydroxy-16α-fluoroandrost-4-ene,11β,17α-dihydroxy-16α-fluoroandrost-4-ene,7α,17β-dihydroxy-16α-fluoroandrost-4-ene,7β,17β-dihydroxy-16α-fluoroandrost-4-ene,3α,17β-dihydroxy-16α-fluoroandrost-4-ene,3β,17β-dihydroxy-16α-fluoroandrost-4-ene,3α,17α-dihydroxy-16β-fluoroandrost-4-ene,3β,17α-dihydroxy-16α-fluoroandrost-4-ene,1α,17β-dihydroxy-16α-fluoroandrost-4-ene,1β,17β-dihydroxy-16α-fluoroandrost-4-ene,2α,17β-dihydroxy-16α-fluoroandrost-4-ene,2β,17β-dihydroxy-16α-fluoroandrost-4-ene,12α,17β-dihydroxy-16α-fluoroandrost-4-ene,12β,17β-dihydroxy-16α-fluoroandrost-4-ene,1α,17α-dihydroxy-16α-fluoroandrost-4-ene,1β,17α-dihydroxy-16α-fluoroandrost-4-ene,2α,17α-dihydroxy-16β-fluoroandrost-4-ene,2β,17α-dihydroxy-16α-fluoroandrost-4-ene,12α,17α-dihydroxy-16α-fluoroandrost-4-ene,12β,17α-dihydroxy-16α-fluoroandrost-4-ene,15β,17β-dihydroxy-16α-fluoroandrost-4-ene,15β,17β-dihydroxy-16α-fluoroandrost-4-ene,17β,18-dihydroxy-16α-fluoroandrost-4-ene,17β,19-dihydroxy-16α-fluoroandrost-4-ene,15β,17α-dihydroxy-16α-fluoroandrost-4-ene,15β,17α-dihydroxy-16α-fluoroandrost-4-ene,17α,18-dihydroxy-16β-fluoroandrost-4-ene,17α,19-dihydroxy-16β-fluoroandrost-4-ene, 3β,17β-dihydroxyandrost-5-ene,3β-hydroxy-7,17-dioxoandrost-5-ene, 3α-hydroxy-7,17-dioxoandrost-5-ene,3β,17-dioxoandrost-5-ene, 3β,17-dioxoandrost-4-ene,3β,17-dioxoandrost-1,4-diene, 3β,7β,17β-trihydroxyandrost-5-ene,3β,7β,17β-trihydroxyandrostane, 3β,16α-dihydroxy-17-oxoandrostane,3α,16α-dihydroxy-17-oxoandrostane, 3β,16β-dihydroxy-17-oxoandrostane,3α,16β-dihydroxy-17-oxoandrostane, 3β,16α,17β-trihydroxyandrostane,3β,16β,17β-trihydroxyandrostane, 3β,16α,17α-trihydroxyandrostane,3β,16β,17α-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane,3α,16β,17β-trihydroxyandrostane or an analog of any of these compoundsthat is (1) 11-oxa substituted or 2-oxa substituted if no double bond ispresent at the 1-2 position, (2) substituted at the 7-position with anα-halogen, β-halogen, α-hydroxyl, β-hydroxyl or oxo moiety, (3) a D-ringhomo analog, (4) a 19-nor analog and/or (5) an analog of any of theforegoing compounds that is substituted with an R¹⁰ substituentdisclosed herein, e.g., wherein the R¹⁰ is a hydroxyl, thiol, optionallysubstituted alkyl or a halogen such as fluorine or bromine at the 1-,2-, 4-, 6-, 9-11-, 12-, 14-, 15- or 16-positions, wherein the R¹⁰, e.g.,the hydroxyl, thiol, optionally substituted alkyl or halogen is presentin the α-configuration or the β-configuration.

109. A method to enhance the healing of a trauma or an acute injury in asubject who has experienced or who is expected to experience a trauma oran acute injury comprising administering an effective amount of acompound to the subject, wherein the compound is (1)3β,17β-dihydroxyandrost-5-ene, 3β,7β,17β-trihydroxyandrost-5-ene, a16-halo analog of either compound, a 16-hydroxy analog of eithercompound, an 11-oxa analog of either compound, a 2-oxa analog of eithercompound, an ester or a carbonate of either compound, a derivative ofeither compound that can convert to either compound by hydrolysis or bymetabolism or (2) a formula 1 compound of any of embodiments 1-66.

110. The method of embodiment 109 wherein the subject will experience orhas experienced an immune suppressive event within about 2-3 weeks orabout 3-4 weeks of the occurrence of the trauma or acute injury, whereinthe immune suppressive event is exposure of the subject to an immunesuppressive amount of ionizing radiation.

111. The method of embodiment 110 wherein the ionizing radiationexposure is about 0.3 Gy to about 30 Gy of the ionizing radiation.

112. The method of embodiment 110 wherein the radiation exposure isabout 0.5 Gy to about 8 Gy of the ionizing radiation.

113. The method of embodiment 109 wherein the subject has experienced animmune suppressive event within 3 weeks of the occurrence of the traumaor acute injury, wherein the immune suppressive event is selected froman immune suppressive amount of an immunosuppressive chemotherapy.

114. The method of embodiment 113 wherein the immunosuppressivechemotherapy is an immunosuppressive cancer chemotherapy, animmunosuppressive antimicrobial therapy or an immunosuppressiveglucocorticoid therapy.

115. The method of embodiment 113 wherein the immunosuppressive cancerchemotherapy is treatment of the subject with an immunosuppressiveamount of cyclophosphamide, 5-fluorouracil or a platinum compoundoptionally selected from cisplatin and carboplatin.

116. The method of embodiment 113 wherein the immunosuppressiveglucocorticoid chemotherapy is treatment of the subject with animmunosuppressive amount of dexamethasone, prednisone, hydrocortisone orcortisol.

117. The method of any of embodiments 109-116 wherein the subject is ahuman or a primate.

118. The method of any of embodiments 109-117 wherein the formula 1compound has the structure

119. The method of embodiment 118 wherein the compound is3β-hydroxy-17β-aminoandrost-5-ene.

120. The method of embodiment 118 wherein the compound is3β-hydroxy-17β-amino-17α-optionally substituted alkyl-androst-5-ene,3,8-hydroxy-9α-fluoro-17β-aminoandrost-5-ene or3,8-hydroxy-17β-amino-19-norandrost-5-ene.

121. The method of any of embodiments 109-117 wherein the compound is3β,17β-dihydroxyandrost-5-ene.

122. A method to modulate the expression of one or more transcriptionfactors or enzymes in a subject who has a dysregulated oxidative stresscondition comprising administering an effective amount of a compound tothe subject, wherein the compound is (1)3β,16α,17β-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane,3β,16α-dihydroxyandrostane-17-one, 3α,16α-dihydroxyandrostane-17-one,3β,17β-dihydroxy-16α-haloandrostane,3α,17β-dihydroxy-16α-haloandrostane,3β,17β-dihydroxy-16α-bromoandrostane,3α,17β-dihydroxy-16α-bromoandrostane,3β-hydroxy-16α-bromoandrostane-17-one,3β-hydroxy-16α-bromoandrostane-17-one hemihydrate,3β,17β-dihydroxyandrost-5-ene, 3β,7β,17β-trihydroxyandrost-5-ene,3β,17β-dihydroxy-16α-haloandrost-5-ene,3α,17β-dihydroxy-16α-haloandrost-5-ene,3β,16α,17β-trihydroxyandrost-5-ene, 3α,16α,17β-trihydroxyandrost-5-ene,an 11-oxa analog of any of these compounds, a 2-oxa analog of any ofthese compounds, a 19-nor analog of any of these compounds, a 9α-fluoroanalog of any of these compounds, or an ester or a carbonate of any ofthese compounds or analogs, or (2) a derivative of any of thesecompounds or analogs that can convert to these compounds or analogs byhydrolysis or by metabolism, or (3) a formula 1 compound of any ofembodiments 1-66.

123. The method of embodiment 122 wherein the compound modulates thelevel or activity of a transcription factor or enzyme selected from oneor more of Nrf2, a Maf protein, a thioredoxin, NQO1, GST, HO 1, SOD2,the catalytic subunit of γGCS, the regulatory subunit of γGCS and xCT.

124. The method of embodiment 122 or 123 wherein the dysregulatedoxidative stress condition is associated with exposure of the subject toa toxin that can cause cell or tissue damage or wherein elevatedoxidative stress is present in one or more of the subject's cell typesor tissues.

125. The method of embodiment 122, 123 or 124 wherein the subject has anacute or chronic inflammation condition, an acute or chronic infectionor a trauma.

126. The method of embodiment 122, 123, 124 or 125 wherein the levels oractivity of one, two or more of Nrf2, a Maf protein, a thioredoxin,NQO1, GST, HO 1, the catalytic subunit of γGCS, the regulatory subunitof γGCS and xCT is increased.

127. The method of embodiment 122, 123, 124, 125 or 126 wherein thecompound is 3β,16α,17β-trihydroxyandrostane,3α,16α,17β-trihydroxyandrostane, 3β,16α-dihydroxyandrostane-17-one or3α,16-dihydroxyandrostane-17-one.

128. A product produced by the process of (1) contacting a F1C(s) and anexcipient or (2) contacting a composition comprising a F1C(s) and one ormore excipients with one or more additional excipients.

129. Use of a compound, composition, formulation or product of any ofembodiments 1-129 or of any species or group of F1Cs disclosed hereinfor the preparation of a medicament. The medicament can be for theprophylaxis or treatment of a disease or condition disclosed herein in asubject having or susceptible to developing the disease or condition.

130. The use of a compound, composition, formulation or product of anyof embodiments 1-129 or of any species or group of F1Cs disclosed hereinto prepare a medicament for use to prevent or to treat, or to ameliorateone or more symptoms associated, with one, two or more acute or chronicdiseases or conditions disclosed herein, e.g., an infection, animmunesuppression condition, an allergy, a cardiovascular condition, ametabolic disorder, a pulmonary condition, a skin condition, aging, atrauma such as a burn or a bone fracture, immune suppression, aneurological or centeral or peripheral nervous system condition ordisorder, an unwanted or pathological inflammatory condition, toxicityor unwanted side-effects of a chemotherapy or of radiation exposure suchas a glucocorticoid treatment or a cancer chemotherapy, an autoimmunedisease or condition, a malignancy or cancer, a pre-malignant conditionor to modulate a mammal's immune response, such as enhancing a Th1response or decreasing a Th2 response, in a subject, e.g., a human or amammal, having the acute or chronic disease or condition or subject todeveloping the acute or chronic disease or condition.

131. The use of embodiment 130, wherein the infection is a viral,bacterial, fungal, yeast or parasite infection, e.g., as describedherein.

132. Use according to embodiment 130 or 131 wherein the medicament isfor intermittently administering the F1C(s) to a subject or deliveringto the subject's tissues the F1C(s), e.g., using an intermittent dosingprotocol disclosed herein.

133. Use of a compound, composition, formulation or product of any ofembodiments 1-129 or of any species or group of F1Cs disclosed herein toprepare a medicament for use to enhance a specific or an innate humoralor cellular response to vaccination or to the presence of 1, 2, 3, 4, 5,6 or more endogenous antigens or epitopes associated with establishingor maintaining a disease or pathogenic agent such as a tumor antigen oran antigen associated with a pathogen.

134. Use according to embodiment 133 wherein the subject's innateimmunity is enhanced.

135. Use according to embodiment 13 or 134 wherein the subject's innateor adaptive immunity is enhanced or wherein an unwanted immune responseis decreased, or wherein number or activity of one, two or more of thesubject's Th1 cells, tumor-infiltrating lymphocytes (TIL cells), NKcells, peripheral blood lymphocytes, phagocytes, monocytes, macrophage,neutrophils, eosinophils, dendritic cells, fibrocytes, astrocytes, gilalcells or stromal cells, e.g., bone marrow, lymph node or spleen stroma,are increased or activated at least transiently (e.g., for at least 10minutes to 10 days or more), which is optionally as measured by, e.g.,enhanced ³H-thymidine uptake compared to untreated controls or by anincrease in the number of the cell type in circulation or demonstrablemovement of the cell type from one tissue or compartment (e.g., skin orblood) to another tissue or compartment (e.g., blood, lymph node,spleen, Peyer's patches, GALT or thymus), or wherein the transcriptionrate, protein level or biological activity of one or more genes in thesubject's NK cells, TIL cells, phagocytes, monocytes, macrophages,neutrophils, eosinophils, dendritic cells, fibrocytes, astrocytes, gilalcells or stromal cells are detectably modulated, e.g., increased (e.g.,as measured by increased enzyme or biological activity of a biomoleculesuch as a nuclear hormone receptor such as an orphan nuclear hormonereceptor, a transcription factor, a chemokine or a cytokine, which isoptionally compared to suitable control cells or tissues).

136. A method to (a) modulate (detectably increase or decrease) theexpression of at least one immune cell antigen by an immune cell in asubject, wherein the immune cell antigen is selected from CD3, CD11c,CD14, CD16, CD19, CD25, CD38, CD56, CD62L, CD69, CD45RA, CD45RO, CD123,HLA-DR, IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNFα, IGF₁ and γIFN,or (b) activate CD8⁺ T cells or CD8⁻ T cells in a subject, wherein theactivation comprises at least transiently enhanced expression of CD25 orCD69 by the T cells, or (c) increase the proportion of CD8⁺ or CD8⁻lymphokine activated killer cells in a subject's CD16+ cells (e.g.,CD8⁺, CD16⁺, CD38⁺ or cells CD8⁻, CD16⁺, CD38⁺), or (d) increase theproportion of (i) CD8⁻, CD16⁺ natural killer cells, (ii) CD8⁺, CD16⁺natural killer cells or (iii) CD8⁻, CD16⁺ cells that mediateantibody-dependent cell-mediated cytotoxicity, or (iv) CD8⁺, CD16⁺ cellsthat mediate antibody-dependent cell-mediated cytotoxicity, or (e)increase the proportion of dendritic cell precursors in a subject'scirculating white blood cells (e.g., Lin⁻, HLA-DR⁺, CD123⁺ or Lin⁻HLA-DR⁺, CD11c⁺ cells) or (f) increase the proportion of CD45RA⁺ T cellsor CD45⁺, R0⁺ T cells in a subject's circulating white blood cells, or(g) change (increase or decrease) the proportion or relative numbers ofCD62L⁺ T cells in a subject's circulating white blood cells, or (h)increase the proportion of CD8⁺ or CD4⁺ T cells that express CD62L in asubject's circulating CD8⁺ or CD4⁺ T cells, or (i) decrease theproportion of CD8⁺ or CD4⁺ T cells that express CD62L in a subject'scirculating CD8⁺ or CD4⁺ T cells, or (j) increase the proportion ofHLA-DR⁺, CD8⁺, CD38⁺ cells in a subject's circulating white blood cells,or (k) decrease the level of IL-4 or IL-10 that is expressed by orpresent in a subject's white blood cells or in a subject's plasma (orthat is expressed after the subject's white cells are stimulated invitro), (l) at least transiently increase the number of dendritic cellprecursors or dendritic cells that are present in a subject's whiteblood cells or in a subject's plasma, or (m) enhance the capacity of animmune cell, e.g., macrophages, CD4⁺ T cells, CD8⁺ T cells to expressIL-2, IL-12 or γIFN or to activate such cells, the method comprisingadministering to the subject an effective amount of a F1C, which isoptionally present in a composition or a formulation comprising 1, 2, 3,4, 5, 6 or more pharmaceutically acceptable excipients. The F1c is anycompound as described herein, e.g., a compound of embodiments 1-66 or inany chemical structure or any compound group.

137. A method to detect or to characterize a biological response (e.g.,increased or decreased cytokine or cell surface antigen expression oractivity, increased numbers of circulating neutrophils, increasedphagocytic activity by phagocytic cells or modulation of a disease orsymptom described herein) associated with the administration of a F1C toa subject comprising (1) obtaining a first biological sample from thesubject and analyzing the sample to obtain a baseline value for theresponse, (2) administering the F1C to the subject to obtain a treatedsubject (3) within about 15 minutes to about 28 days after administeringthe F1C, obtaining a second biological sample from the treated subjectand analyzing the sample to obtain a treated value for the response, and(4) optionally comparing the control information with the experimentalinformation to detect the presence, absence, relative magnitude orabsolute magnitude of the biological response.

138. The method of embodiment 137 wherein the biological response ismodulation of CD8⁺ T cells, CD4⁺ T cells, CD8⁺ lymphokine activatedkiller cells, CD8⁻, CD16⁺ natural killer cells, circulating dendriticcell precursors, circulating dendritic cells, tissue dendritic cellprecursors, tissue dendritic cells, CD8⁺ lymphokine activated killercells, CD8⁻ lymphokine activated killer cells, CD8⁻, CD16⁺ naturalkiller cells, CD8⁺, CD16⁺ natural killer cells, CD8⁻, CD16⁺ cells thatmediate antibody-dependent cell-mediated cytotoxicity, CD8⁺, CD16⁺ cellsthat mediate antibody-dependent cell-mediated cytotoxicity, CD45RA⁺ Tcells, CD45RA⁺, CD45RO⁺ T cells, CD45RO⁺ T cells, CD8⁺, CD62L T cells,CD4⁺, CD62L⁺ T cells or HLA-DR⁺, CD8⁺, CD38⁺ T cells, monocytes,macrophages, glial cells or astrocytes, or wherein the biologicalresponse is at least transient modulation of an immune cell antigen oran immune accessory cell antigen (e.g., an adhesion molecule at thesurface of endothelial cells or a cytokine receptor at the surface of Tcells or B cells or a CD molecule, an interleukin or a cytokine,optionally selected from CD16, CD25, CD38, CD62L, CD69, CD45RA, CD45RO,IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, TNFα, IGF₁ and γIFN).

139. A kit comprising a formulation that comprises a unit dosage or amultiple dosage comprising a F1C, e.g., any compound described or withinany structure disclosed herein, and one or more excipients wherein theformulation is dispensed in a suitable closed container, wherein the kitoptionally further comprises a label that provides information about oneor more of (1) the F1C's chemical structure, (2) any recommended dosingregimen, (3) any adverse effects of administering the F1C to a subjectthat are required to be disclosed and (4) the amount of the F1C that ispresent in each unit dose or in the entire container.

140. A method to treat a symptom or condition associated with one ormore delayed adverse or unwanted effects of radiation exposure ortherapy in a subject in need thereof comprising administering to thesubject, or delivering to the subject's tissues, an effective amount ofa compound of formula 1, wherein the F1C is administered or delivered tothe subject's tissues beginning at least 2 weeks after the subject hasbeen exposed to a dose of radiation that will cause or could potentiallycause the one or more delayed adverse or unwanted effects of theradiation exposure, or wherein the F1C is administered or delivered tothe subject's tissues beginning at least 2 weeks after the subject hasbeen exposed to at least one subdose of a planned course of radiationexposures that will cause or could potentially cause the one or moredelayed adverse effects or unwanted effects of the radiation exposure.

141. The method of embodiment 140 wherein the subject has received, oris anticipated to receive, a total radiation dose of at least about 0.5Gy to about 300 Gy, wherein the subject received the radiation dose in asingle dose or in two or more divided doses, e.g., a total radiationdose of at least about Gy 1 to about 12 Gy, or at least about Gy 1 toabout 8 Gy.

142. The method of embodiment 140 or 141 wherein the symptom orcondition associated with one or more delayed adverse effect ofradiation is one or more of encephalopathy, myelopathy, nausea,vomiting, diarrhea, acute inflammation, e.g., of the lung, chronicinflammation, e.g., of the lung, edema, pain, headache, depression,fever, malaise, weakness, hair loss, skin atrophy, skin ulceration, skinlesion, keratosis, telangiectasia, infection, hypoplasia, atrophy,fibrosis, pneumonitis, bone marrow hypoplasia, hemorrhage, leukopenia orthrombocytopenia.

143. The method of embodiment 140, 141 or 142 wherein the symptom orcondition associated with one or more delayed adverse or unwanted effectof the radiation exposure or therapy is caused by or associated withradiation damage to one or more of bone marrow cells, bowel epithelium,bone marrow, testicles, ovaries, brain nerves or tissue, peripheralnerves, spinal cord nerves or tissue or skin epithelium.

Variations and modifications of these embodiments, the claims and theremaining portions of this disclosure will be apparent to the skilledartisan after a reading thereof. Such variations and modifications arewithin the scope and spirit of this invention. All citations herein areincorporated herein by reference in their entirety. All citations hereinare incorporated herein by reference with specificity.

EXAMPLES

The following examples further illustrate the invention and they are notintended to limit it in any way. Variations of these examples that areincluded in the invention may include, e.g., any of the F1Cs describedherein or parts or all of any of the methods, formulations, treatmentprotocols and/or assays described herein.

Example 1

Treatment of cytopenia. Primates treated to induce neutropenia orthrombocytopenia are used to characterize their response to treatmentwith a F1C. Mitigation of cytopenia, e.g., neutropenia orthrombocytopenia, by the F1C is observed. In an exemplary protocol,Cynomolgus monkeys of about 3.5-8 years of age and weighing about 2.5 to8 kg are dosed at 35 mg/kg with carboplatin (sterile 10 mg/mL solutionin 0.9% sodium chloride) by intravenous infusion over 30 minutes.Beginning at 1 or 2 days after the carboplatin infusion, each animal isdosed once daily or once every other day with the F1C for 1, 2, 3, 4, 5,6, 7, 8, 9 or 10 days, e.g., once per day for 5 consecutive daysbeginning 2 days after carboplatin infusion. The F1C is in a suitablesterile solution or suspension formulation in suitable excipients, e.g.,a suspension containing 0.1% w/v carboxymethyl-cellulose, 0.9% w/vsodium chloride and 0.05% v/v phenol. The suspension contains micronizedF1C. Control animals receive the formulation without any F1C. Theanimals are dosed with the F1C subcutaneously in the interscapularregion of the back or intramuscularly in the thigh at a dosage of about1-45 mg/kg, e.g., 1.25, 2.5, 7.65 or 42.5 mg/kg of the F1C. Bloodsamples of about 1-1.5 mL are withdrawn at various times, e.g., on days−5 (pre-carboplatin), −2 (pre-carboplatin), 1 (4 hr post-dosing), 3, 7,10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 32 and 36 days, for analysissuch as neutrophil, platelet, reticulocyte, erythrocyte counts. Thedegree of reduced time and/or severity of cytopenia such as neutropeniais then observed in F1C treated and control animals. F1C that are usedinclude 3β-hydroxy-17β-aminoandrost-5-ene,3β-hydroxy-17β-aminoandrost-1,5-ene,3β-hydroxy-17β-methylaminoandrost-5-ene, 3β,17β-dihydroxyandrost-5-ene,3β,17β-dihydroxyandrost-1,5-diene,3β,17β-dihydroxy-16α-fluoroandrost-5-ene,3β,7β-dihydroxy-17β-aminoandrost-5-ene,3β,16α-dihydroxy-17β-aminoandrost-5-ene and 2-oxa or 11-oxa analogs ofthese compounds.

Example 2

Treatment of ionizing radiation exposure. The effect of selected F1Cs onsurvival of lethally-irradiated female B6D2F1 mice were compared tocontrol animals treated with vehicle alone. The animals were exposed to10 Gy of total body irradiation at 2.5 Gy/min using a ¹³⁷Cs source.Groups of 12 animals were used in a total of 5 groups. For Groups 1, 2,3, and 5, test article was administered as a 100 μL volume, bysubcutaneous injection, for three consecutive days, with the first doseadministered 2 to 4 hours following exposure to radiation. For Group 4,test article was administered as a 50 μL volume, by intramuscularinjection for three consecutive days. The formulation was a suspensioncontaining 0.1% w/v carboxymethyl-cellulose, 0.9% w/v sodium chlorideand 0.05% v/v phenol. The formulations were agitated to uniformlyresuspend the F1C before syringing, and injected into animals within afew minutes of drawing into the syringe to prevent settling in thesyringe.

The groups of animals were treated as follows. Group 1 received vehicleonly by daily subcutaneous injection for 3 consecutive days. Group 2received 0.6 mg in 100 μL of a suspension of3β,17β-dihydroxyandrost-5-ene by daily subcutaneous injection for 3consecutive days. Group 3 received 3.0 mg in 100 μL of a suspension of3β,17β-dihydroxyandrost-5-ene by daily subcutaneous injection for 3consecutive days. Group 4 received 0.6 mg in 50 μL of a suspension of3β,17β-dihydroxyandrost-5-ene by daily intramuscular injection for 3consecutive days. Group 5 received 0.6 mg in 100 μL of a suspension of3β-hydroxy-17β-aminoandrost-5-ene by daily subcutaneous injection for 3consecutive days.

Survival of the animals was monitored for 21 days after irradiation andthe following results were obtained. The number of surviving animals isshown for day 6, 7, 12 and 21. The results show that the F1Cs increasedthe rate of survival of subjects that were exposed to an otherwiselethal dose of ionizing radiation.

Day Group 6 7 12 21 1 vehicle control 12 11 4 1 2 0.6 mg s.c. 12 11 10 73 3.0 mg s.c. 12 12 9 7 4 0.6 mg i.m. 12 12 11 9 5 0.6 mg s.c. 12 12 1211

Example 3

Cystic fibrosis treatment. Treatment with a F1C is conducted on humancystic fibrosis (“CF”) patients, e.g., 18 years of age or older, who mayhave two or more of the following characteristics: (1) sweat chloride≧60 mEq/L, e.g., by quantitative pilocarpine iontophoresis test, (2)homozygosity for the F508 genetic mutation, or heterozygosity for 2well-characterized mutations, e.g., as described herein, associated withCF, (3) FEV₁≧40% predicted at screening, (4) SaO₂≧90% at screening, (5)ability to perform pulmonary function tests and (6) clinical stability,with no evidence of acute upper or lower respiratory tract infection orcurrent pulmonary exacerbation. The treatment regimen consists of 1, 2,3, 4 or 5 consecutive days of once daily dosing of a F1C or placeboequivalent followed by a 40-day observation period. Daily dosages areabout 10-150 mg/day, e.g., about 25 mg/day, 50 mg/day, 75 mg/day or 100mg/day. The F1C is administered as described herein such as by aparenteral route, e.g., intramuscular or subcutaneous delivery, or bytransmucosal delivery, e.g., buccal or sublingual. A follow-up visitwill occur 6 weeks after the last treatment course to collect finalsamples for safety and activity. Patients receive, e.g., 3 treatmentcourses over a 14-week period, 6 treatment courses over a 28-week periodor more courses of treatment over a longer period. F1Cs that are usedinclude 3β-hydroxy-16α-bromo-17-oxoandrostane,3β-hydroxy-16α-bromo-17-oxoandrostane hemihydrate,3β,16α-dihydroxy-17-oxoandrostane, 3α,16α-dihydroxy-17-oxoandrostane,3β,16α,17β-trihydroxyandrostane or 3α,16α,17β-trihydroxyandrostane oranother F1C disclosed herein. The patients are optionally monitored forthe status of their condition or in improvement of one or more CFsymptoms after dosing, e.g., reduction in the numbers of neutrophils inbronchiolar or alveolar lavage samples, e.g., about a 30%, 40%, 50% orgreater reduction, or levels of one or more CF-related inflammationmarkers, e.g., reduced levels or activity of IL-6, IL-8, IKK-β kinase orneutrophil elastase, or in the reduced occurrence, severity orprogression of infections such as a Burkholderia (Pseudomonas) cepaciainfection.

Example 4

Enhancement of tissue repair and stem cells in damaged tissues. Mice(8-10 week old male BDF1 mice) are held for 2 weeks in individuallyventilated cages in an SPF (H. Pylori-negative) barrier unit. The miceare divided into groups of about 6 as follows. Group 1 is exposed to 13Gy of X-radiation. Group 2 is treated with a F1C at about 24 hoursbefore radiation, exposed to 13 Gy of X-radiation and dosed on the sameday about 2 hours later with the F1C, followed by 2 consecutive days ofonce daily dosing with the F1C. Group 3 is treated with the F1C oncedaily for 3 consecutive days, the first dose being administered about 2hr following a 13 Gy irradiation. Group 4 receives vehicle without theF1C 24 hr prior to irradiation and then once daily for 3 consecutivedays, the first dose being administered 2 hr following irradiation.Group 5 is an unirradiated, untreated control group. All mice areanalyzed at 4 days post-irradiation. The small intestine is removed andplaced in Carnoy's fixative. Samples are paraffin embedded and processedfor histology.

The number of surviving and/or regenerating intestinal crypts in eachtreatment group, and the control groups, are scored. The mean number ofcrypts per cross-section in each group is determined. Surviving cryptwidths is measured to correct for size-induced scoring anomalies. Foreach mouse, about 10 cross-sections of intestine is analysed (see, e.g.,C. S. Potten et al., Cell Proliferation 36:115-129 2003) to obtain thenumbers of repopulating intestinal crypts. The capacity of the F1C toenhance repopulation is observed as increased numbers of repopulatingcrypts in animals treated with a F1C compared to irridiated controls.F1Cs such as one or more of 3β-hydroxy-17β-aminoandroat-5-ene,3α-hydroxy-17β-aminoandroat-5-ene,3β-hydroxy-17β-aminoandroat-1,5-diene,3α-hydroxy-17β-aminoandroat-1,5-diene, 3β,17β-dihydroxyandroat-5-ene,3β,17β-dihydroxy-16α-haloandroat-5-ene and3β,17β-dihydroxy-16α-haloandroat-1,5-diene are tested.

Example 5

Human and primate virus treatment protocol. Humans infected with avirus, e.g., HCV, HBV or a retrovirus such as HIV1 or HIV2 or primatesinfected with a virus such as HCV, HIV1, HIV2, SIV or SHIV₂₂₉ aretreated with a F1C formulation. Daily dosages of about 0.05 to about 25mg/kg are administered daily or on an intermittent basis. The F1C isadministered, e.g., orally, by subcutaneous injection, by intramuscularinjection or by transmucosal delivery. A typical intermittent dosingprotocol for human patients comprises daily dosing of about 0.1-5 mg/kgof the F1C for 1, 2, 3, 4, 5 or 6 days, followed by no dosing for about1, 2, 3, 4, 5, 6, 7 or 8 weeks, daily dosing again for 1, 2, 3, 4, 5 or6 days, no dosing for about 1, 2, 3, 4, 5, 6, 7 or 8 weeks andoptionally repeating this dosing schedule as desired, e.g., for 3, 4, 5,10, 15 or more rounds of dosing. A related dosing protocol involvesdosing on every 2^(nd) or 3^(rd) day to deliver 2, 3, 4, 5 or 6 doses ofthe F1C, no dosing for about 2, 3, 4, 5, 6, 7 or 8 weeks and optionallyrepeating this dosing schedule as desired, e.g., for 3, 4, 5, 10, 15 ormore rounds of dosing. Typical daily F1C doses in human treatmentprotocols is about 5 mg to about 1000 mg, usually about 10-150 mg. Dailydoses can vary depending on the route of F1C administration and on thepatient's weight and clinical condition, with oral administrationusually requiring higher daily doses than parenteral or transmucosaladministration.

In treating a viral infection such as a human HIV1 or HIV2 infection,one can optionally monitor one or more aspects the patient's response,e.g., periodic assay for viral load or for the level or activity of agiven immune cell type or a biomolecule described herein such as CD4⁺ Tcells, CD123⁺ dendritic cells, IL-6, IL-10 or TNFα. Changes in celltypes, viral load or biomolecules can be transient, e.g., detectablychanged over a period of about 2-48 hours, or sustained, e.g.,detectably changed for about 3-6 days or about 1-8 weeks. Other aspectsof the patient's response may also be monitored such as the incidence,severity or rate of progression of symptoms or associated conditionssuch as coinfection, fatigue, weight loss or side effects of othersuitable therapies. In retrovirus-infected patients that are treatedwith the F1C, the rate or progression of a clinically significantcoinfection by Mycobacteria or Pneumocystis is generally reduced,including for patients with a CD4⁺ T cell count of less than about 100cells/mm³ or less than about 75 cells/mm³.

Example 6

Four-day in vivo protocol for inhibition of Plasmodium berghei. Theassay consists of the inoculation of parasitised erythrocytes on thefirst day of the experiment (D₀), followed by an injection of the F1C,which is also administered on the 2^(nd), 3rd and 4^(th) days of theprotocol. On the 5^(th) day, blood films are taken and antimalarialactivity is assessed either by calculating parasitemia, or by scoringparasite numbers on a predetermined scale (i.e., 1-5). W. Peters Ann.Trop. Med. Parasitol. 64:25-40, 1970.

The protocol is summarized as follows. Five female TO mice are used pertest group. P. berghei HP15 ANKA parasites are collected by cardiacpuncture using a heparinised syringe from a donor mouse having a 30+%parasitaemia. The blood is diluted with diluting agent (50% HIFCS+50%sterile PBS) to a final concentration of 1% parasitaemia or 1×10⁷infected erythrocytes per 0.2 mL of the infecting suspension. Each mouseis inoculated intravenously, which produced a more uniform infectionrate than intraperitoneal administration of 0.2 mL of the infectingsuspension. Test compounds are prepared at doses of 100 mg/kg in (16.7%DMSO+83.3% Celacol). The steroid formulations are administeredintraperitoneally 2 hours after parasite inoculation. The compounds areadministered once a day starting on D₀, and continued on the followingthree days. Blood films are made from tail blood on the day after thelast dosing of compound and the blood is fixed with 100% methanol andstained with 10% Giemsa. Parasitaemias are scored on a scale of 0-5,where 5 is equal to the control.

An inoculum of 1% parasitaemia 1×10⁷ erythrocytes/mL, 0.2 mL per mouse(female strain TO mice), is delivered by intravenous injection. Drugadministration commenced 2 hours after inoculation on Day 1 andcontinued for 3 days. The results are shown below from blood films fromall 20 mice on Day 5 when parasitaemias are assessed.

Example 7

Stimulation of phagocytosis. The capacity of F1Cs to influencephagocytosis of Plasmodium parasite-infected RBC is examined usingadherent human monocytes. The parasitemia level is about 8-10% and humanmonocytes are obtained from buffy coats from blood as follows.Peripheral blood mononuclear cells are separated from freshly collectedplatelet-poor buffy coats discarded from blood samples of healthy adultdonors of both sexes. Separated cells are washed once with luke-warm PBSsupplemented with 10 mM glucose (PBS-G) and resuspended at 5×10⁶cells/mL in ice-cold RPMI 1640 medium supplemented with 23 mM NaHCO₃ and25 mM Hepes, pH 7.4 (RMBH). Dynabeads M450 Pan B and Pan T (Dynal) areadded to cells in a 4:1 ratio for 20 min at 4° C. B-lymphocytes andT-lymphocytes are removed as specified by the manufacturer. Theremaining monocytes are washed 2 times in RMBH, resuspended in AIM Vcell culture medium (Gibco) at 1×10⁶ cell/mL. The monocyte layer iscollected, washed with PBS-G at 37° C. and resuspended in AIM V mediumat 1×10⁶ cells/mL. Purified cells are >90% monocytes as assessed by CD14expression.

Phagocytosis of opsonized parasitized RBC (PE) is determined as follows.Phagocytosis of fresh-serum opsonized PE is initiated by mixing 10PE/monocyte. Suspensions are briefly centrifuged (150×g for 5 sec atroom temperature) to improve contact between PE and monocytes. To avoidattachment of monocytes after centrifugation and during the wholeincubation period, cells are kept in suspension at 5×10⁶ cells/5 mL AIMV medium in 6 cm diameter teflon bottom dishes (Heraeus) in a humidifiedincubator (95% air, 5% CO₂) at 37° C. On average, at least 90% of themonocytes phagocytose PE, as assessed by microscopic inspection. Controlcells are kept under similar conditions without phagocytosis.Quantitative assessment of phagocytosis is performed by a previouslydescribed bioluminescence method (E. Schwarzer, et al., Br. J. Haematol.1994 88: 740-745).

Erythrocyte treatments and parasite cultures are as follows. Fresh blood(Rh+) is used to isolate erythrocytes (RBC). Washed RBC are infectedwith schizont/trophozoite parasite stages (Palo Alto strain,mycoplasma-free). Stage specific parasites are isolated by thePercoll-mannitol method. Briefly, normal schizont-stage parasitized RBC(SPE) separated on Percoll-mannitol gradient (parasitemia>95% SPE) aremixed with RBC suspended in growth medium (RPMI 1640 medium containing25 mmol/L Hepes, 20 mmol/L glucose, 2 mmol/L glutamine, 24 mmol/LNaHCO₃, 32 mg/L gentamicin and 10% AB or A human serum, pH 7.30) tostart synchronous cultures at selected hematocrit values. The inoculumparasitemia is adjusted to 20% normal SPE for isolation of ringparasitized RBC (RPE) and to 5% normal SPE for isolation oftrophozoite-stage parasitized RBC (TPE). At 14-18 hours after inoculumparasites are at ring-stage in the first cycle; at 34-33 hours,parasites are at trophozoite-stage in the first cycle; and at 40-44hours after inoculum parasites are at schizont-stage in the first cycle.RPE, TPE and SPE are separated on Percoll-mannitol gradients. Theparasitemia is usually 8-10% RPE, and >95% TPE. Nonparasitized andparasitized RBC are counted electronically. To assess total parasitemiaand relative contribution of RPE, TPE and SPE, slides are prepared fromcultures at indicated times, stained with Diff-Quik™ parasite stain andabout 400-1000 cells are examined microscopically.

The effect of a formula 1 compound such as F1C in parasitized RBC isexamined using various concentrations of the compound, e.g., F1C, e.g.,0.5 μM, 1 μM, 10 μM, 25 μM and 50 μM. Trophozoite-parasitized RBC,schizont-parasitized RBC or ring-parasitized RBC are examined asdescribed.

Example 8

Cyclodextrin formulation. A cyclodextrin formulation containing a F1C isprepared by mixing a sulfobutyl β-cyclodextrin and the F1C in one ormore liquids such as ethanol, DMSO, N-methylpyrrolidine, pyridine orwater. The sulfobutyl β-cyclodextrin contains one or more butylsulfonate or —O—(CH₂)₄—SO₃ ⁻Na⁺ moieties, typically about 5, 6 or 7 percyclodextrin molecule. F1Cs that contain a positive charge areespecially helpful in forming complexes with the multiple negativecharges of sulfobutyl cyclodextrin. For parenteral formulations, themaximum concentrations could be achieved at about the maximumcyclodextrin concentration that is still syringable, about 50% w:v. TheF1C can be added to a solution of sulfobutyl β-cyclodextrin at a molarratio of about 1:1, e.g., 0.5:1 to about 2:1, and stirred with orwithout heat for up to about 1 week to form the complex. The solution isoptionally filtered or sterilized before filling in vials or injectiondelivery by any route. The vials can be sterilized by radiation or bysterile filtration. An exemplary preparation is made using 500 grams ofsulfobutyl β-cyclodextrin (about 230 mmoles) combined with about 230mmoles of the F1C. Solutions containing about 20-80 mg/mL of the F1C aretypically obtained. For pharmaceutical formulations, the complex isprepared under GMP compliance conditions. The dried complex is preparedby lyophilization and can be reconstituted, e.g., using sterile 0.9%NaCl. The cyclodextrin complex can also be dried for preparation offormulations for oral or transmucosal administration or reconstitutedwith water for parenteral delivery, e.g., by subcutaneous orintramuscular injection. F1Cs that are used include3β,17β-dihydroxyandrost-5-ene, 3β,17β-dihydroxy-16α-fluoroandrost-5-ene,3β,7β,17β-trihydroxyandrost-5-ene,3β-hydroxy-3α-methyl-17β-aminoandrost-4-ene,3α-hydroxy-3β-methyl-17β-aminoandrost-4-ene and3β-hydroxy-17β-aminoandrost-5-ene.

Example 9

Inhibition of inflammation. The capacity of formula 1 compounds to limitor inhibit inflammation or symptoms of inflammation is shown usinganimal models for inflammatory bowel disease. In an exemplary protocol,groups of 3 male Wistar rats (180±20 grams) fasted for 24 hours before2,4-dinitrobenzene sulfonic acid (DNBS) or saline challenge are used.Distal colitis is induced by intra-colonic instillation of 0.5 mL of anethanolic solution of DNBS (30 mg in 0.5 mL of a 30% ethanol in salinesolution) after which 2 mL of air is injected through the cannula toensure that the solution remained in the colon. The volume used is 0.1mL per injection of 2 and 20 mg/mL of a F1C in a liquid formulation,which is administered by subcutaneous injection once a day for 6 days.The formulation contained 100 mg/mL of the F1C in a non-aqueoussuspension, e.g., 2% benzyl alcohol w/v, 0.1% Brij 96 w/v and equalvolumes of PEG 300 and propylene glycol. Concentrations of 2 mg/mL and20 mg/mL are obtained by diluting the 20 mg/mL formulation with vehiclethat lacked the F1C.

The first F1C dose is given 30 minutes after DNBS challenge.Sulfasalazine (30 mg/mL in 2% Tween 80 in distilled water) isadministered orally (PO) once a day (10 mL/kg/day) for 7 days, the firsttwo doses beginning 24 hours and 2 hours before DNBS challenge. Thepresence of diarrhea is recorded daily by examining the anal area.Animals are fasted for 24 hours prior to being sacrificed. Animals aresacrificed on day 7 or day 8 and their colons are removed and weighed.Before removal of the colon, signs of adhesion between the colon andother organs are recorded. Also, the presence of ulcerations is notedafter weighing of each colon. The “net” change of colon-to-body weight(BW) ratio is normalized relative to saline-challenged baseline group. A30% decrease in “net” colon-to-body weight ratio is consideredsignificant.

Example 10

Modulation of delayed type hypersensitivity. The capacity of F1Cs tomodulate delayed type hypersensitivity (DTH) is determined in mice.Groups of five female BALB/cByJ mice (20-25 grams) are anesthetized and100 μL of a 3% solution of oxazolone is applied on day 0 to the shavedabdomen and dried. Seven days later, on day 7, the mice are challengedby applying 5 μL of oxazolone topically to each side of the right ear.The F1C (at about 20-100 mg/mL) in vehicle is administered bysubcutaneous injection (2 mg/day) one time on day 6, 24 hours before theoxazolone challenge. The vehicle as a non-aqueous suspension of the F1Cin, e.g., 2% benzyl alcohol w/v, 0.1% Brij 96 w/v and equal volumes ofPEG 300 and propylene glycol.

Dexamethasone in saline (0.2 mg/mL) is administered daily for 9 days(day −1 to 7), first dose 24 hours before sensitization, last dose atchallenge by subcutaneous injection (0.01 mg/dose, 50 μL/injection). OnDay 8, 24 hours following the oxazolone challenge, both the right andleft ear thicknesses are measured using a micrometer caliper and thedifferences are determined. The differential ear thickness is measuredas an indicator of the DTH response to topical oxazolone challenge. TheDTH response is expressed as the difference in the thickness (mm)between the right and the left ears for each animal.

The differential ear thickness in animals receiving vehicle alone is0.225 mm and treatment with dexamethasone (high dose) orcyclophosphamide reduced the DTH response (0.144 mm and 0.092 mm,respectively).

Example 11

Reversal of immunosenescence. Healthy aged (20-month) orimmunologically-mature (3-month) BALB/c mice are vaccinated withhepatitis B surface antigen (HbsAg) (2 μg; Recombivax-HB; Merck) andAlum (2.75 μg). The aged mice are vaccinated with the antigen and alsoreceived a single subcutaneous injection of either 0.3 mg or 3.0 mg ofselected F1Cs or the vehicle (placebo control).

Blood samples are collected 14, 21 and 34 days after treatment and thesera are analyzed by ELISA to determine the concentration ofHbsAg-specific IgG (total IgG). In addition, samples obtained on day 21are analyzed to determine the concentration of HbsAg-specific IgG1 andIgG2a subclasses. The results can be summarized as average valuesobtained with blood samples collected 21 days after vaccination ofgroups of 8 mice. Subcutaneous injection is performed after shaving thehair from the thighs of each mouse. The injected volume is 50 μLcontaining 3.0 mg or 0.3 mg of compound or placebo, and for vaccinepreparation. The vehicle control consists of carboxymethyl-cellulose(0.5%) in saline (0.9%). Antibody titers are determined by ELISA.

Treatment of aged, vaccinated animals with the F1Cs, can result inhigher anti-HbsAg IgG titers than aged animals receiving the vaccinationonly. Such results would show that the F1Cs can enhance immune responseto antigen challenge in immune senescent animals.

The serum samples are also analyzed for the titers of HbsAg-specific,IgG1 or IgG2a immunoglobulin subclasses. A bias to IgG1 is seen in agedmice and this is considered symptomatic of immune senescence or asuboptimal immune response associated with immune senescence. TheIgG1/IgG2a ratio is an indicator of immune status. Th2 cellspredominantly assist in the generation of humoral immunity, while Th1cells enhance, e.g., cellular immunity. Humoral immunity (Th2) becomespredominant with age, while the decreasing cellular (Th1) immunity leadsto increased susceptibility to, e.g., infectious diseases.

To examine the secondary antibody response, 42 days after the initialexposure to HbsAg, serum samples are taken from the mice and these aretested for anti-HbsAg IgG. At this time-point, vaccine-specific IgGtiters are either low or undetectable. Three days later (45 days afterfirst vaccination), the mice are injected again with HbsAg in alum, butthis time, none of the mice receive any F1C (secondary vaccination).Serum samples collected 7 days and 14 days after the second exposure toHbsAg vaccine are assayed for anti-HbsAg antibody. In the young mice, amarked increase in specific antibody is seen in response to the secondvaccination. In aged mice that had receive no F1C with the first HbsAginjection, levels of anti-HbsAg are measured. The data is analyzed forincreases in anti-HbsAg titers following secondary vaccination in agedanimals that had been treated with a F1C in conjunction with the firstHbsAg exposure.

Example 12

Vaccine adjuvant activity. Selected F1Cs are used to modulate the immuneresponse to an antigen(s) such as malaria antigens encoded by DNAexpression vectors. Antigens such as a Plasmodium, e.g., P. yoelii, P.falciparum, P. vivax or P. berghei, circumsporozoite or merozoiteprotein are used to immunize a subject. The F1C is administered on thesame day or a day or two before antigen challenge. Suitable antigens,expression vectors and their delivery to a subject have been described.See, e.g., S. L. Hoffman et al., Vaccine 1994 12:1529-1533, R. Weiss etal., Infect. Immunity 2000 68:5914-5919, J. C. Rayner et al., Proc.Nat'l. Acad. Sci. U.S.A. 2000 97:9648-9653, S. Scheiblhofer et al., Eur.J. Immunol. 2001 31:692-298. The capacity of the compounds to enhanceimmune responses to the antigens by, e.g., measuring cytotoxic Tlymphocytes or antibody titer after delivery of the formula 1 compoundand immunization with an antigen(s). Typically the immune response ismeasured at about 10 days to about 21 days after a primary immunization.Methods to measure immune responses are essentially as described hereinor in appropriate cited references. DNAs that encode an antigen(s) thatis associated with, e.g., an infectious agent or a tumor describedherein may be used in these assays.

Example 13

Suppression of TNF-α induced adhesion molecule expression. Therecruitment of lymphocytes to areas of inflammation and angiogenesisinvolves specific receptor-ligand interactions between cell surfaceadhesion molecules (CAMs) on lymphocytes and the vascular endothelium.The adhesion process, in both normal and pathological settings, followsa multi-step cascade that involves intercellular adhesion molecule-1(ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelialleukocyte adhesion molecule-1 (E-selectin) expression on endothelialcells (EC). The expression of these molecules and others on the vascularendothelium determines the efficiency with which leukocytes may adhereto the local vasculature and extravasate into the local tissue duringthe development of an inflammatory response. The local concentration ofcytokines and growth factor participate in the modulation of theexpression of these CAMs.

Tumor necrosis factor alpha (TNF-α), is a proinflammatory cytokine andstimulates all three CAMs on endothelial cells. It may be involved in awide variety of inflammatory responses, often resulting in apathological outcome. The capacity of a formula 1 compound to mediate asuppression of TNF-α induced CAM expression can be examined. A modifiedELISA assay which uses Ecs as a solid phase absorbent is employed tomeasure the amount of CAM expression on TNF-α treated Ecs whenco-stimulated with a member of the FGF family of proteins. To performthe experiment, human umbilical vein endothelial cell (HUVEC) culturesare obtained from pooled cord harvests and maintained in growth medium(EGM-2, Clonetics, San Diego, Calif.) supplemented with 10% FCS and 1%penicillin/streptomycin in a 37° C. humidified incubator containing 5%CO₂. HUVECs are seeded in 96-well plates at concentrations of about1×10⁴ cells/well in EGM medium at 37° C. for 18-24 hrs or untilconfluent. The monolayers are subsequently washed 3 times with aserum-free solution of RPMI-1640 optionally supplemented with 100 U/mLpenicillin and 100 mg/mL streptomycin, and treated with a given cytokineand/or growth 5 factor(s) for 24 h at 37° C. Following incubation, thecells are then evaluated for CAM expression.

HUVECs are grown in a standard 96 well plate to confluence. Growthmedium is removed from the cells and replaced with 90 μL of 199 Medium(10% FBS). Samples for testing and positive or negative controls areadded to the plate in triplicate (in 10 μL volumes). Plates areincubated at 37° C. for either 5 h (selectin and integrin expression) or24 h (integrin expression). Plates are aspirated to remove medium and100 pL of 0.1% paraformaldehyde-PBS (with Ca⁺⁺ and Mg⁺⁺) is added toeach well. Plates are held at 4° C. for 30 min. Fixative is then removedfrom the wells and wells are washed 1× with PBS(+Ca,Mg)+0.5% BSA anddrained. Do not allow the wells to dry. 10 μL of diluted primaryantibody is added to the test and control wells. Anti-ICAM-1-Biotin,Anti-VCAM-1-Biotin and Anti-E-selectin-Biotin are used at aconcentration of 10 pg/ml (1:10 dilution of 0.1 mg/ml stock antibody).Cells are incubated at 37° C. for 30 min. in a humidified environment.Wells are washed ×3 with PBS (with Ca, Mg) and 0.5% BSA. Then add 20 pLof diluted ExtrAvidin-Alkaline Phosphotase (1:5,000 dilution) to eachwell and incubate at 37° C. for 30 min. Wells are washed ×3 with PBS(with Ca, Mg) and 0.5% BSA. 1 tablet of p-Nitrophenol Phosphate pNPP isdissolved in 5 mL of glycine buffer (pH 10.4). 100 pl of pNPP substratein glycine buffer is added to each test well. Standard wells intriplicate are prepared from the working dilution of theExtrAvidin-Alkaline Phosphotase in glycine buffer: 5 pL of each dilutionis added to triplicate wells and the resulting AP content in each wellis 5.50 ng, 1.74 ng, 0.55 ng, 0.18 ng. 100 μl of pNNP reagent is then beadded to each of the standard wells. The plate is incubated at 37° C.for 4 h. A volume of 50 μL of 3M NaOH is added to all wells. The resultsare quantified on a plate reader at 405 nm. The background subtractionoption is used on blank wells filled with glycine buffer only. Thetemplate is set up to indicate the concentration of AP-conjugate in eachstandard well. Results are indicated as amount of bound AP conjugate ineach sample.

Example 14

Effects on the CNS. The effects of the formula 1 compounds on memory,learning, motor function or the status of a neurological condition orneurodegeneration condition are assayed using standard methods. Forexample, aged, two year old mice are tested in the Morris water mazeprocedure by training the mice to locate a pedestal in less than 15seconds in three consecutive trials. Immediately upon completion oftraining one group of mice is treated with a formula 1 compound (5-30mg/kg) and a second group is treated with a placebo. The treatmentcomprises one, two or three intraperitoneal, subcutaneous, intramuscularor intravenous injections of the formula 1 compound and the vehicleplacebo. The injections are given once per day. Two weeks aftertreatment, the time to rescue is timed in the Morris water mazeprocedure and the control result is compared to the placebo control. Theuse of Morris water maze and other procedures to measure the effect ofvarious conditions or compounds on learning, memory or neurologicalconditions have been described, see e.g., R. Gerlai Trends Neurosci.1996, 19:177-181, J. L. W. Lau et al., Proc. Nat'l. Acad. Sci. 2001,98:4716-4721, U.S. Pat. Nos. 6,348,489, 6,251,942 and 6277886.

Scopolamine induced amnesia is examined essentially as follows. Groupsof 13 to 16 C57BL76 mice (about 35 gm) are trained in the Morris watermaze procedure to locate a pedestal in less than 15 seconds in threeconsecutive trials. Immediately upon completion of training the mice ineach of three groups are treated with scopolamine (1 mg/kg), scopolamineplus a formula 1 compound at one or more dosages (e.g., about 5-50mg/kg), and scopolamine plus a placebo. The treatment comprises one, twoor three intraperitoneal, subcutaneous, intramuscular or intravenousinjections of the formula 1 compound and the vehicle placebo. Theinjections are given once per day. Six days after treatment the averagetime (sec) to rescue is timed using the Morris water maze procedure andthe results from each group are compared. Results for a F1C such as3α,17β-dihydroxy-16α-fluoroandrost-5-ene or3β-hydroxy-17β-aminoandrost-5-ene are optionally compared to the resultsthat are obtained in these protocols using another control compound,e.g., (S)-(−)-N-propargyl-1-aminoindan or nefiracetam, or another F1C.

Example 15

Ischemia treatment. The capacity of F1Cs to limit injury associated withischemia and reperfusion is determined in an animal model essentially asfollows. Male Sprague-Dawley rats weighing 130-170 g are randomlyassigned to no pre-treatment, vehicle pre-treatment or formula 1compound pre-treatment using one or more dosages, e.g., about 1-10mg/kg. Animals are treated with vehicle or F1C the day before and theday of surgery. Anesthesia is induced with intraperitoneal pentobarbital(60-70 mg/kg). The rats are placed on a heating pad, and bodytemperature is maintained at about 36° C. Detection of the cremastermuscle on its neurovascular pedicle is performed essentially accordingto conventional techniques, e.g., Anderson, G. L. et al., MicrovascularRes. 1988 36:56-63, Siemionow, M. et al., Microcirc. Endoth. Lymphatics1991 7:183-197, Siemionow, M. et al., J. Hand Surgery 1993 18A:963-971.

Briefly, a skin incision is made from the anterior iliac spine to thetip of the scrotum. The testis with cremaster muscle intact is thendissected away from the scrotum. An opening of 1 cm is made on theventral surface of the cremaster, and the testis and spermatic cord areremoved. Under a microscope, the neurovascular pedicle, consisting ofthe pubic-epigastric arteries, vein, and genitofemoral nerve, is thencompletely isolated by dissecting to the origin of the vessels from theexternal iliac artery and vein. The front wall of the cremaster musclesac is opened and the island cremaster muscle flap is prepared forintravital videomicroscopy. The rat is secured on a tissue bath, and thecremaster muscle flap is spread over the coverglass in the opening atthe bottom of the bath and fixed with 5-0 silk sutures. It is thentransilluminated from below, using a fiber optic tungsten lamp. Themuscle is kept moist and covered with impermeable plastic film. Thetissue bath, designed specifically for temperature control, is filledwith 0.9% saline and the temperature maintained at between 35-36° C. Themicroscope is equipped with a color video camera. The video image of themicrocirculation is displayed on a 19″ monitor, where the finalmagnification is 1800×. Measurement of microvascular activity isrecorded after isolation of the muscle to establish the pre-ischemiabaseline. After proper positioning of clamps to completely shut downblood flow to the muscle flap, the duration of the ischemic period issix hours. Following removal of clamps to induce reperfusion injury,activity in the microvasculature is measured at e.g., 30, 60 and 90minutes post-reperfusion. In all experimental subjects, ischemia isfollowed by reflow and then by an initial period of flow of bloodthrough the microcirculation. This burst of circulatory activity isfollowed by marked reperfusion injury that induces loss of flow.

One or more of the following parameters are used to evaluate the stateof the cremaster muscle microvasculatory system prior to ischemia andafter reperfusion. The density of perfused capillaries in each of threeflap regions is measured by counting the number of flowing capillariesin proximity to the preselected post-capillary venule. Nine visualfields of capillaries are counted at each postcapillary venule site, fora total of 27 fields per cremaster muscle flap.

A leukocyte count in postcapillary venules is taken using video scans ofthree pre-selected post-capillary venules in proximal, middle and distalflap regions. For each venule, the number of leukocytes rolling throughthe lumen, the number adhering to the endothelium and the numbermigrating across the endothelium over a two-minute period are recorded.Results are optionally obtained for rollers, strikers and diapedesis.

Red blood cell velocities in first order and second order arterioles aremeasured. Red blood cell velocities are recorded in the main arteriolesof the cremaster flap using an optical Doppler velocimeter. Results areobtained for velocity of venous and arterial blood.

In an exemplary protocol, six rats are untreated and six rats arepre-treated with vehicle. Under conditions of six hours of ischemia and90 minutes of reperfusion, the absolute number of rolling, sticking andtransmigrated leukocytes is determined within 60 minutes of reperfusionand at 90 minutes. Rats are pre-treated with a formula 1 compound bysubcutaneous injection the day before and the day of surgery to measureany protective effect of the therapy. One or more of the threeparameters are determined and are compared to normal values. Theendothelial-adherent properties compared to baseline values areoptionally determined, using numbers of rolling, sticking andtransmigrating leukocytes. Red cell velocities in second orderarterioles are compared to normal rates of flow at, e.g., 90 minutespost-reperfusion.

Example 16

Pulmonary vasoconstriction. The capacity of F1Cs to limit hypoxiainduced pulmonary vasoconstriction is demonstrated using an animal modelessentially as follows. Isolated perfused ferret lungs are anestablished animal model to study secondary pulmonary hypertension. Inbrief, male ferrets are anesthetized with intraperitoneal pentobarbitalsodium and the chest is opened. Stainless steel cannulae are secured inthe left atrium and pulmonary artery, and the pulmonary artery and theaorta are ligated. The lungs are perfused with a mixture of autologousblood and Krebs-Henseleit buffer in a circulating manner at a constantrate of about 85 mL/min. The perfusion circuit includes a perfusatereservoir, a roller perfusion pump, filter, and a heat exchanger. Theperfusion system is made of, e.g., tygon tubing, which is used forconnections and for passage through the perfusion pump. The temperatureof the perfusate is kept about 37-38° C. and the pH is maintained at7.35 to 7.40 by adding sodium bicarbonate to the reservoir as needed.The venous reservoir is placed below the lowermost portion of the lung.

The lungs are ventilated with a hypoxic gas mixture of 5% CO₂, 4% O₂,and 91% N₂ by a tracheotomy with a Harvard animal respirator for 30minutes. The animals are ventilated with a tidal volume of 30 mL, at arate of 18 breaths/min. and with 2 cm of H₂O positive end-expiatorypressure. For measurements, pulmonary arterial, left atrial and trachealpressures are monitored using Gould Statha P231 D pressure transducersor an equivalent connected to the inflow circulation and recorded on,e.g., a Grass polygraph. After 30 minutes of ventilation with hypoxicgas mixture, a formula 1 compound in a dose between about 5-25 mg/kgbody weight is added to the reservoir, and perfusate is allowed toperfuse the ferret lungs for 1.5 hours. Pulmonary artery pressure ismeasured until the end of the experiment, i.e., a total of two hours.Pressure that remains at or near basal level indicates the vasodilatoryeffect of the F1C in pulmonary circulation that is otherwise constrictedin response to hypoxia. The effects of the F1Cs can be compared to theeffects and duration of nitric oxide, a therapeutic agent that isoptionally used in this model as a control.

Example 17

Hematopoiesis modulaton. Enhanced hematopoiesis is observed in mammalswith immune injury from, e.g., radiation exposure or from animmunosuppressive chemotherapy. In an example, animals are used todemonstrate the effect of formula 1 compounds on hematopoiesis afterimmune system injury due to radiation. Hematopoiesis in the murineimmune system after radiation is optionally used because of the similarresponses of murine and human hematopoiesis to drugs and toxic insults(see, e.g., J. H. Hendry and B. I. Lord, editors, Radiation toxicology:Bone marrow and leukaemia 1995 Taylor & Francis Inc., London).

In an exemplary protocol, B6D2F1/J female mice (Jackson Laboratory, BarHarbor, Me.), 18-24 weeks of age, 22-30 g body weight, are obtained andheld in quarantine for two weeks. Up to 10 mice are housed in sanitized46×24×15 cm polycarbonate boxes with filter covers (MicroIsolator; LabProducts, Inc, Maywood, N.J.) on autoclaved hardwood chip bedding. Miceare given feed and acidified (pH 2.5) water freely. The animal holdingroom is maintained with conditioned fresh air at approximately 21° C.and 50° (±10%) relative humidity and with a 12-h light/dark fullspectrum lighting cycle.

Mice are placed in ventilated Plexiglas containers and exposedbilaterally to gamma-radiation from a ⁶⁰Co source. Exposure time isadjusted so that each animal received a midline tissue-absorbed dose of1-12 Gy at a nominal dose rate of 0.4 Gy/min at ambient temperature.Using a standardized technique, the midline dose rate is measured byplacing a 0.5 cc tissue-equivalent ionization chamber at the center of a2,5-cm diameter cylindrical acrylic mouse phantom. The tissue-air ratio,defined as the ratio of the dose rate measured in the phantom to thedose rate in free air, for this array is about 0.96. Variation withinthe exposure field is less than about 4%. Dosimetric measurements aremade in accordance with the American Association of Physicists inMedicine protocol for the determination of absorbed dose fromhigh-energy photon and electron beams (Med. Phys. 1983 10:741-771).Sham-irradiated mice are treated in the same way as the irradiatedanimals, except that the animals are not irridiated.

Various formula 1 compounds are formulated with a suitable vehicle(e.g., PEG-400) or sterile 0.9% NaCl (saline) optionally containingother excipients such as a cyclodextrin. The compounds are injectedsubcutaneously in a volume of about 0.1 mL or they are delivered orallyor they are administered by another route. Doses typically range fromabout 1 mg/kg to about 350 mg/kg, e.g., about 1, 10, 20, 40, 80, 160 or320 mg/kg.

Blood (0.6-1.0 mL) is obtained from halothane-anesthetized mice bycardiac puncture using a heparinized syringe attached to a 21-gaugeneedle. Blood is collected in EDTA-containing sample tubes. Mice areeuthanized by cervical dislocation after blood collection. White bloodcell (WBC), red blood cell (RBC) and platelet (PLT) counts are performedusing, e.g., a Hematology System 9000 (Biochem Immunosystems).Wright-stained blood smears from the same samples are made fordifferential counts of neutrophils and lymphocytes by light microscopy.

Hemopoietic progenitor cells committed to granulocyte-macrophagedifferentiation (GM-CFC) are assayed by a single-layer modification of adouble-layer semisolid agar technique essentially as described (Patchenet al. Adv. Space Res. 1992 12:223-248). For example, femoral marrow isextracted and cell suspensions are prepared by flushing with 3 mL ofMcCoy's 5A medium containing 10% heat-inactivated fetal bovine serum(HIFBS; Hyclone, Logan, Utah). Each cell suspension represented a poolof marrow from four femurs, i.e., both femurs from each of two mice. Thetotal number of nucleated cells in each suspension is determined with,e.g., a Coulter counter. The agar-medium mixture consisted of equalvolumes of 0.66% agar and double-strength supplemented CMRL 1066 medium(Gibco, Grand Island, N.Y.). The medium is supplemented with finalconcentrations of 10% HIFBS, 5% tryptic soy broth, 5% heat-inactivatedhorse serum, antibiotics, and L-serine. One milliliter of theagar-medium mixture is added to each 35-mm plastic Petri dish (twodishes per suspension) and mixed with 50 μL of 0.1 ng/μL recombinantmouse GM-CSF (Genzyme, Cambridge, Mass.). Cell suspensions are thenmixed into the agar-medium mixture to a final concentration of 0.5×10⁵cells/mL for unirradiated animals, and 1.0×10⁵ or 1.5×10⁵ cells/mL forirradiated animals to ensure sufficient colonies per plate forquantitation. Control experiments are done to confirm linearity ofcolonies at cell concentrations of 0.5−1.5×10⁵ cells/mL. Colonies (>50cells) are counted after seven days incubation in a 37° C. humidifiedenvironment containing 5% CO₂. The average of the counts for the twodishes is taken as the value for each pool. About six animals are usedper group in each of two experiments.

For histological examination of myeloid hyperplasia in bone marrow afteradministration of the formula 1 compound, mice are euthanized withhalothane, tissues are immersed in formalin, bones are decalcified androutine H&E-stained 6-μm paraffin sections are prepared.

For induced-infection studies, a clinical isolate of K. pneumoniae,capsule type 5 (strain AFRRI 7), that is kept frozen at 70° C. in skimmilk, is grown overnight at 35° C. on Trypticase Soy Agar(Becton-Dickinson, Sparks, Md.). Five typical colonies are inoculatedinto 8 mL of brain heart infusion broth (Becton-Dickinson) and incubatedovernight at 35° C. Two milliliters of this overnight suspension isinoculated into 95 mL of prewarmed brain heart infusion broth. Theculture is incubated at 35° C. with shaking for approximately 2.5 h. Theoptical density of bacterial growth is monitored with aspectrophotometer at a wavelength of 550 nm. Late log-phase cells areished and suspended in cold saline to yield 109 viable bacteria per mL.Appropriate dilutions for inoculations are made in cold saline.

To induce a bacterial infection, all mice are injected sc with K.pneumoniae four days after sham-irradiation or irradiation whencirculating leukocytes are depressed. Mice are inoculated sc rather thaniv or ip, to establish infection leading to sepsis, but not rapid septicshock. After sc inoculations of K. pneumoniae in the mice, the infectionremains largely localized to the injection site. K. pneumoniae are notdetectable in blood of inoculated mice until a few hours before death.

Different doses of the bacteria are inoculated for each of threeradiation dose levels (0, 1 or 3 Gy) to approximate the LD_(95/30)(radiation dose that is lethal for 30-95% of animals), because theeffects of radiation on hematopoiesis and susceptibility to infectionare dependent on the dose of radiation. The LD_(95/30) for bacteria ateach radiation dose is calculated from probit analysis. The actual dosesare estimated by dilution plating of inocula onto Trypticase Soy Agarand incubating overnight at 35° C. Since different bacterial doses areexpected to be needed for different radiation doses, the LD_(95/30) isestimated for each group and different mortality rates are observed inthe vehicle-injected control groups. Bacterial doses forinduced-infection experiments are prepared and calculated in the samemanner.

Animals are checked frequently, e.g., once or twice daily, six or sevendays per week, to monitor survival and to euthanize mice that are in amoribund state. To verify that mortality in the induced-infectionexperiments is associated with K. pneumoniae injection, heart blood fromrecently deceased animals (or moribund animals euthanized by cervicaldislocation) is cultured overnight at 35° C. on Columbia sheep bloodagar plates (Becton-Dickinson, Sparks, Md.). Colonies are identified asK. pneumoniae by a suitable means, e.g., Biolog analysis.

For histological analysis of bone marrow, coded slides are scored blindusing a five-level semiquantitative scale and the results analyzed witha randomization t-test to obtain exact P-values. Thirty-day survivalvalues are compared using the generalized Savage (Mantel-Cox) procedure(BMDP Statistical Software, Inc, Los Angeles, Calif.). To calculate dosereduction factors (DRFs), probit analysis is performed on mortalitydata.

To characterize the potency of formula 1 compounds to ameliorateradiation-induced defects in hematopoiesis, mice are exposed tobilateral whole-body gamma-radiation and receive a dose of 3 Gy (or aresham-irradiated). One hour after irradiation or sham-irradiation, miceare injected with 320 mg/kg 3β,17β-dihydroxyandrost-5-ene (“AED”) orPEG-400 vehicle. Between-group differences in blood cell elements, e.g.,neutrophils, GM-CFC and platelets are generally determined. Irradiationresults in a decrease in neutrophils at about four days after radiationcompared to sham-irradiated animals.

Example 18

Antiglucocorticoid effects of formula 1 compounds. A series of tests isrun in triplicate using BALB/c mouse spleen cells to demonstrate theeffect of the F1Cs and hydrocortisone (“Hycort”) on cellularproliferation in the absence of a mitogen. Cultures of spleen cells areprepared and F1Cs are added at, e.g., 0.1, 0.5, 1 and 5 μM. Suitablecontrols are used. Twenty four hours after setup, about 50 μCi[³H]-thymidine is added to each cell. Four to six hours later, the cellsare harvested and counted on a scintillation counter.

Spleen cells are obtained from normal BALB/c mice and prepared as asingle cell suspension at a concentration of about 1×10⁷ cells/ml inRPMI 1640 supplemented with 2 mM L-glutamine, 5×10⁻⁵ M2-mercaptoethanol, 20 μg/ml gentamycin-sulfate, and 1% Nutridona-NS(Boehringer-Mannheim). Individual aliquots of cells are then pulsed for30 minutes at 37° C. with selected concentrations of formula 1compounds. After pulsing, the cells are washed several times in balancedsalt solution, resuspended in fresh medium, and then dispensed into24-well culture plates with a stimulatory concentration of anti-CD3(e.g., Leo et al. Proc. Natl. Acad. Sci. U.S.A., 84:1374 (1987)). Aftera 24-hour incubation period, culture supernatants are harvested forassessment of proliferation or cytokine production, e.g., IL-2, IL-3 orIL-4 using, e.g., the method of Mossman (J. Immunol. Meth. 65:55(1983)). 100% control titers of IL-3, IL-2 or IL-4 from normalstimulated splenocytes are obtained, exemplary values may be about 640units/mL or IL-2 and 160 units/mL for IL-4.

Effects of formula 1 compounds and Hydrocortisone on Proliferation inthe Presence of a Mitogen. A series of spleen cell cultures is run usinga formula 1 compound and/or hydrocortisone with cell cultures to whichconcanavalin A is added. Preliminary tests on cultures to whichconcanavalin A is added at concentrations of 10.0, 5.0, 2.5 and 1.0ng/mL. All tests on the effects of invention compounds on culturesstimulated with concanavalin A are performed with concanavalin A at,e.g., about 2.5 ng/mL. A mitogen such as ConA generally increases cellproliferation and the glucocorticoid steroid (“GCS”) can decreaseproliferation. Detectable partial or complete reversal of the inhibitoreffects of hydrocortisone indicate an anti-glucorticoid effect by theformula 1 compounds.

Effect of formula 1 compounds on IL-3 production. Exemplary formula 1compounds are characterized for their effect on the level of thecytokine IL-3 expression by spleen cells in tissue culture and for theircapacity to reverse the effects of a GCS in IL-3 expression. The spleencell cultures are prepared in accordance with the general method above.After 30 hours the level of IL-3 in the supernatants of the cultures wasmeasured using the IL-3 ELISA kit manufactured by EndoGen Inc., Boston,Mass. A GCS such as hydrocortisone will generally suppress theproduction of IL-3 and the invention compounds are examined for theircapacity to modify this effect. The IL-3 expressed by cells in culturemay be recovered from the media containing IL-3 by known methods such assingle or sequential reverse-phase HPLC steps on a preparative HPLCcolumn. (See Urdal, et al., J. Chromatog. 296:171 (1984) and U.S. Pat.No. 5,128,450).

Example 19

Treatment of neurodegenerative conditions. Experimental allergicencephalomyelitis (EAE), is demyelinating disease of the central nervoussystem with many pathological and clinical similarities with multiplesclerosis (MS). EAE is thus a recognized animal model for humanautoimmune conditions such as MS. F1Cs such as3β,7β-dihydroxy-17β-aminoandrost-5-ene and3β-hydroxy-17β-aminoandrost-5-ene are tested for their capacity to delaythe onset of EAE or to reduce its symptoms. Female SJL mice (5 animalsper group) are immunized with 150 to 200 μg of PLP-139-151 peptide/CFAto induce EAE. Starting 7 days before injection of the peptide, theanimals are given daily injections (s.c.) of the compounds (3.0 mg) in0.1 mL vehicle, or vehicle alone for 33 days. The vehicle consisted of asuspension of the formula 1 compound in saline andcarboxymethylcellulose. Delayed onset, reduced peak clinical score (from5.2±0.6 to 2.8±1.8) and cumulative disease index (>60%) of EAE, andprevention of or significant attenuation of relapses are measured.Reduced numbers of PLP-139-151 specific T cell responses and reducednumbers of TNF-α producing cells in the CNS indicate reduced diseaseprogression or severity. Reduced production of autoimmune Th-1associated cytokines, is consistent with restoration of a more normalTh-1/Th-2 immune balance and/or with reduction of inflammation in thismodel.

The efficacy of the formula 1 compounds to treat other autoimmuneconditions can be determined by incorporating their use with suitableanimal models or assay methods, e.g., collagen-induced arthritis as amodel for human autoimmune polyarthritis (e.g., L. K. Myers et al.,Clin. Immunol. 2002, 102:185-191, A. Matejuk et al., Endocrinology 2002,143:313-319, S. Thornton et al., J. Immunol. 165:1557-1563). The effectof the compounds on markers of inflammation such as TNFα, MIP-1β, IL-13,IL-15, IL-17 or IL-18, e.g., reduced expression or activity, isoptionally observed in any autoimmune or inflammatory condition.

Example 20

Modulation of transcription. The effect of 16α-bromoepiandrosterone(“BrEA”) on transcript levels in cells in vitro was studied using amicroarray to allow simultaneous monitoring of the expression of manygenes to allow detailed analysis of the molecular pathways involved inbiological responses to the compound.

In general, microarray technology works by covalently linking short DNAsequences that are complementary to the transcripts of many differentgenes on a single slide or array chip. mRNAs from test and controlsamples are generated and labeled with one or more colored fluorescentdyes or probes. The probes are hybridized with the array, which is thenscanned by laser. The color and intensity of the fluorescent signal ateach spot denotes relative expression level of each gene. The capacityof other F1Cs described herein, e.g., a F1C in compound group 1, 2, 3, 4or 5, to modulate gene expression is characterized in a similar manner.

The array used in the experiment described below, contained about 12,000known genes. The experiment used U937 human promonocytic leukemia cellsthat differentiate to monocyte/macrophage cells in the presence ofphorbol-12-myristate-13-acetate (“PMA”). The U937 cells were PMA treatedand then exposed to BrEA for 1 hr, 2 hrs, or 4 hrs, followed bybacterial lipopolysaccharide (“LPS”) stimulation for 1 hr, 2 hrs or 4hrs. The level of transcripts of the genes on the array was measured atthe time points using RNA prepared from BrEA-treated and control (noBrEA) cells. U937 cells were plated at 1×10⁵ cells/mL in the presence of3 ng/mL PMA (Sigma, Catalog #P-8139) for 48 hrs. Cells were then treatedwith either 10 μM BrEA or DMSO (vehicle) for 1 hr, 2 hr, and 4 hrs. Ateach time point, cells were harvested and total RNA was extracted usingQiagen Rneasy kit according to manufacturer's specification. Total RNAsamples were then analyzed by Mergen Ltd. (San Leandro, Calif.www.mergen.com) to perform microarray assay.

For the microarray assay, Dnase-treated total RNA (20 micrograms) wasreverse-transcribed using an oligo[(dT)₂₄ T7 promoter]₆₅ primer(consisting of the nucleotide binding sequence for the T7 RNA polymerasefollowed by 24 thymidine nucleotides). This was followed by secondstrand synthesis. The reaction mixture was then treated with Rnase I todigest the remaining RNA. The double-stranded cDNA was phenol-chloroformextracted and used as template for in vitro transcription (T7MEGAscript, Ambion, Inc.) to generate biotin-labeled cRNA probes. Theseprobes were hybridized overnight at 30° C. with continuous agitation toMergen's ExpressChip H05 DNA Microarray System (catalog number H05-001)containing 12,000 genes. The arrays were then washed, and hybridizedprobes were detected using Mergen's cyanine-3 fluorescent dye-conjugatedprotein. Chips were imaged using an Affymetrix 417-418 formAffymetrix/Genetic MicroSystems (www.affymetrix.com) and spot intensitywas quantitated using ImaGenefrom BioDiscovery Inc.(www.biodiscovery.con).

The results showed that BrEA was capable of substantially up-regulatinga number of genes. A number of genes were differentially regulated byBrEA based on two criteria: 1) the expression level of any particulargene in a BrEA-treated sample is at least two-fold higher than that ofthe control-treated sample; and 2) the expression level of anyparticular gene in a BrEA-treated sample is significantly higher thanbackground. The up-regulation of many of these genes most apparent at 4hr after treatment, at which time roughly 700 genes were within theabove criteria. Some examples are shown in the following list. Theratios given in the list are from BrEA treated cells compared to controlcells not treated with BrEA.

Ratio* UniGene ID UniGene symbol HO5 gene description 5.3 Hs.460 ATF3Activating transcription factor 3 5.4 Hs.78546 ATP2B1 ATPase, Ca++transporting, plasma membrane 1 10.2 Hs.2128 DUSP5 Dual specificityphosphatase 5 9.7 Hs.155119 EHD1 EH-domain containing 1 9.6 Hs.75765GRO2 GRO2 oncogene 124.7 Hs.89690 GRO3 GRO3 oncogene 7.8 Hs.274402HSPA1B Heat shock 70 kD protein 1B 32.0 Hs.177781 MGC5618 Hypotheticalprotein MGC5618 6.6 Hs.75063 HIVEP2 immunodeficiency virus type Ienhancer- binding protein 2 21.5 Hs.727 INHBA Inhibin, beta A (activinA, activin AB alpha polypeptide) 53.0 Hs.81134 IL1RN Interleukin 1receptor antagonist 27.5 Hs.126256 IL1B Interleukin 1, beta 7.6 Hs.12503IL15RA Interleukin 15 receptor, alpha 131.8 Hs.98309 IL23A Interleukin23, alpha subunit p19 16.9 Hs.50640 SSI-1 JAK binding protein 7.7Hs.24684 KIAA1376 KIAA1376 protein 6.9 Hs.164719 KIAA1726 KIAA1726protein 7.1 Hs.151988 MAP3K5 Mitogen-activated protein kinase kinasekinase 5 25.5 Hs.301183 MAIL Molecule possessing ankyrin repeats inducedby lipopolysaccharide (MAIL), homolog of mouse 30.0 Hs.75607 MACSMyristoylated alanine-rich protein kinase C substrate (MARCKS, 80K-L)6.4 Hs.109281 NAF1 Nef-associated factor 1 11.3 Hs.81328 NFKBIA Nuclearfactor of kappa light polypeptide gene enhancer in B-cells inhibitor,alpha 26.1 Hs.77729 OLR1 Oxidised low density lipoprotein receptor 11348.4 Hs.2050 PTX3 Pentaxin-related gene, rapidly induced by IL-1 beta14.5 Hs.80205 PIM2 Pim-2 oncogene 9.2 Hs.239138 PBEF Pre-B-cellcolony-enhancing factor 5.4 Hs.3407 PKIG Protein kinase (cAMP-dependent,catalytic) inhibitor gamma 6.6 Hs.103755 RIPK2 Receptor-interactingserine-threonine kinase 2 29.2 Hs.183601 RGS16 Regulator of G-proteinsignalling 16 5.3 Hs.115521 REV3L REV3 (yeast homolog)-like, catalyticsubunit of DNA polymerase zeta 5.9 Hs.27018 LOC51285 Ris 8.4 Hs.82085SERPINE1 Serine (or cysteine) proteinase inhibitor, clade E (nexin,plasminogen activator inhibitor type 1), member 1 9.0 Hs.1087 STK2Serine/threonine kinase 2 5.9 Hs.167503 STAT5A Signal transducer andactivator of transcription 5A 40.4 Hs.72918 SCYA1 Small induciblecytokine A1 (I-309, homologous to mouse Tca-3) 67.3 Hs.75703 SCYA4 Smallinducible cytokine A4 (homologous to mouse Mip-1b) 174.0 Hs.75498 SCYA20Small inducible cytokine subfamily A (Cys- Cys), member 20 7.0 Hs.271387SCYA8 Small inducible cytokine subfamily A (Cys- Cys), member 8(monocyte chemotactic protein 2) 39.7 Hs.318885 SOD2 Superoxidedismutase 2, mitochondrial 17.4 Hs.112259 TRG@ T cell receptor gammalocus 15.0 Hs.2134 TRAF1 TNF receptor-associated factor 1 10.3 Hs.17839GG2-1 TNF-induced protein 17.4 Hs.101382 TNFAIP2 Tumor necrosis factor,alpha-induced protein 2 5.1 Hs.211600 TNFAIP3 Tumor necrosis factor,alpha-induced protein 3 1733.0 Hs.29352 TNFAIP6 Tumor necrosis factor,alpha-induced protein 6 *Ratio of BrEA treated cells compared to controlcells not treated with BrEA

As seen from the data shown above, BrEA was capable of inducing anincrease in the level of transcription of a number of genes. Theseincreases ranged from about a 2-fold increase to an increase of greaterthan about 1700-fold. For some genes, levels of mRNA increased from anearly undetectable level to a very high level. For genes that aremodulated by the formula 1 compounds, the level of mRNA, protein or oneor more biological activities associated with the gene product can thusinclude an increase or a decrease of at least about 3-fold, at leastabout 5-fold, at least about 10-fold, at least about 20-fold, at leastabout 50-fold or at least about 100-fold. This increase or decrease mayoccur for 1, 2, 3, 4, 5, 6 or more of the affected genes. Pathwaysthrough which BrEA may mediate its effects include one or more of thefollowing. At 1 hr, transcripts of USF1, c-Fos, EGR1, and Cul1 wereincreased. Cul1 activates NFkB1p50. At 2 hrs, USF1 increases FCARtranscript levels. At 4 hrs, c-Fos/C/EBPβ stimulate transcription ofRANTES, NFκB1 p50, IL6, ICAM1, TSG (TNFAIP6), and IL1β. NFκB1p50/RelAinduces IL-2Rα, IL6, GRO2 and GRO3. At 5 hrs, USF1 increases HO1transcript levels. Alternatively, at 4 hrs, Jun B is also increased, andc-Fos/JunB & JunB/ATF3 increase c-Jun. c-Fos/c-Jun increases ATF-3,MMP1, TNFα and TSG-6 (TNFAIP3). Elevated AP1 or EGR1 increases TGFβ.ATF-3/c-Jun & c-Fos increase MMP3. Activity associated with the presenceof the NFkBp50/RelA complex increases IL-8. NFkBp50, STAT5A and STAT5Binduce IL2Rα (interleukin-2 receptor a). STAT5B Induces CDKN1A. IFNγR2induces T-bet. Other formula 1 compounds will generally affect one ormore of these pathways in a similar manner.

In general, the genes showing the greatest increases in expressionbelong to the following families: chemokines (GRO2, GRO3, SCYA1, SCYA4,SCYA20, and SCYA8), cytokines and their receptors (IL1RN, IL1B, IL15RA,and IL23A), TNFα-related/induced genes (TRAF1, GG2-1, TNFAIP2, TNFAIP3,and TNFAIP6), and members of several different signal transductionpathways (e.g. MAP3K5, STAT5A, SSI-1, RGS16, and NFκBIA). Changes in theexpression level of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more ofthese genes or other genes described herein are useful as a screeningassay or method to analyze other test compounds or other formula 1compounds. The assay can identify the relative potency of the testcompound compared to the activity of BrEA or a formula 1 compound, orthe assay can identify a distinct subset of the activities seen withBrEA or another formula 1 compound, for example.

As discussed above, BrEA was found to increase immunity in anon-inflammatory cellular context, e.g., in the absence of LPS here, butBrEA decreased inflammation when the cells were in the presence of astrong inducer of inflammation. Thus, BrEA was capable of mediating bothapparently contradictory activities by context-specific regulation ofactivities. The formula 1 compounds act differently in differenttissues, depending on the physiological condition of cells or tissues ina subject or cells or tissues in vitro. In multiple systems, both inanimals and in humans, the formula 1 compounds appear to drive immunefunction toward homeostasis. This was observed in the context of HIVwhere BrEA stimulated immune response in a condition of immunesuppression. But, in the context of autoimmunity, the formula 1compounds generally limit unwanted autoimmune responses. Depending onthe state of the target cell, genes will be regulated in a manner thatoptimizes desired immune responses while limiting unwanted immuneresponses. Responses to formula 1 compounds in resting cells (e.g. atvaccination) will be different than responses in activated cells (e.g.chronic inflammation).

Screening assays using a formula 1 compound or another compound wouldinclude any method that measures the expression level of one or more ofthese genes in the presence of a test compound as compared to theirexpression in the absence of the test compound and/or compared to theexpression seen with BrEA or another formula 1 compound. This can bedone by microarray essentially as described above, as well as by mini orcustom array on a focused list of genes (such as the list above andoptionally including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more ofthe genes disclosed herein), quantitative PCR assays such as eXpresProfiling or real-time PCR (www.altheatech.com), and Northern blotanalysis. In some cases, when a target gene product is a secretedprotein, such as SCYA1, measuring protein level in the culture media forcells in tissue culture by ELISA could also be used as a screeningassay. Also, cells for this type of analysis can be obtained from asubject who has been dosed with a formula 1 compound or another testcompound. In this case, the cells could be obtained from blood, e.g.,white blood cells, or from bone marrow, lymph tissue, spleen tissue orthymus tissue.

It will be appreciated that the methods and compositions of the instantinvention can be incorporated in the form of a variety of embodiments,some of which are disclosed herein. It will be apparent to the artisanthat other embodiments exist and do not depart from the scope of theinvention. Thus, the described embodiments are illustrative and shouldnot be construed as restrictive.

For any of the uses of formula 1 compounds described herein, e.g., inany of the examples above, the results or biological effects that areobtained using individual formula 1 compounds are optionally compared tothe results or biological effects that are obtained using a referenceformula 1 compound such as 3β,17β-dihydroxyandrost-5-ene,3β,7β,17β-trihydroxyandrost-5-ene or BrEA. A reference F1C can serve asa positive control or negative control for modulation of genetranscription or activity. Other known modulators of a gene whosebiological activity is associated with a symptom or clinical conditionof interest could also be used as a reference control with or without areference F1C control. Such comparisons provide guidance for using theformula 1 compounds in the different methods or clinical conditions.Such comparison information allows, e.g., tailoring of dosages, dosingschedules, routes of administration or drug interactions with othertherapeutic treatments in any selected application for the F1Cs.

Example 21

The effect of F1Cs on transcript or gene product levels in cells invitro is studied in vitro using a cell type of interest, e.g., themurine macrophage cell line designated RAW264.7 (“RAW” cells). For theRAW cells, the cells are maintained in a suitable medium, e.g., RPMI1640 supplemented with 10% FBS, standard Penn/Strep antibiotic solutionand 2 mM glutamine. The T1C is dissolved in a suitable solvent, e.g.,DMSO or pyrrolidone, to generate a 10 mM stock solution. For DMSOsolutions, appropriate dilutions are made to give a F1C finalconcentration in culture media of about 1 nM to about 10 μM, with afinal DMSO content of no more than 0.1% v/v. The cells are induced withLPS at 100 ng/ml (stock solution in water, diluted in serum-free culturemedia).

In a typical protocol, on day 0 the cells are plated at a density toreach a sub-confluent state of greater than about 75% confluency on thefollowing day. For 6-well plates, about 500,000 to 700,000 cells/wellare plated. On the following day, day 1, the cells are treated with theF1C or vehicle, e.g., DMSO, with or without LPS, for selected times,e.g., 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48 hours. Afterincubation, cells are harvested with a cell scraper and total RNA isextracted to generate samples for PCR analysis. 1 mL of culture media isoptionally saved at −20° C. for future ELISA analysis to determine genetranscript levels. On day 2, cells are harvested after, e.g., 24 hr ofF1C in DMSO treatment. LPS induction is started in cells pre-treatedwith F1C in, e.g., DMSO. Exemplary treatment conditions and time pointsfor cell harvesting are as follows:

No treatment 0 hr 24 hr DMSO + LPS 1 hr 4 hr 8 hr 24 hr F1C 10 μM + LPS1 hr 4 hr 8 hr 24 hr F1C 1 μM + LPS 1 hr 4 hr 8 hr 24 hr F1C 10 nM + LPS1 hr 4 hr 8 hr 24 hr DMSO 24 hr + LPS 1 hr 4 hr 8 hr 24 hr F1C 10 μM 24hr + LPS 1 hr 4 hr 8 hr 24 hr F1C 1 μM 24 hr + LPS 1 hr 4 hr 8 hr 24 hrF1C 10 nM 24 hr + LPS 1 hr 4 hr 8 hr 24 hr

Exemplary genes of interest that can be analyzed by this or a similarprotocol include 1, 2, 3, 4, 5, 6 or more of iNOS (inducible nitricoxide synthase), eNOS (constitutive nitric oxide synthase), COX-2(cycloxygenase-2, PGE2 synthase), IκBβ, TNFα, IL-1β, IL-1Ra (interleukin1 receptor antagonist), NFκB1 (p105), NFκB2 (p49/p100), IL-6, MCP-1(monocyte chemoattractant protein-1 or CCL2), MIP-2 (macrophageinflammatory protein-2), MMP9 (matrix metalloproteinase 9), gelatinaseB, HO-1 (heme oxygenase 1), HIF1α (hypoxia inducible factor 1, alphasubunit), GCLC (gamma glutamylcycleine synthetase catalytic (heavy)subunit or γGCS-hs), GCLM (gamma glutamylcycleine synthetase modifier(light) subunit or γGCS-1s), xCT (cystine/glutamate exchangetransporter), NQO1 (NAD(P)H: quinone oxidoreductase 1), TXNRD1(thioredoxin reductase 1), EBBP (estrogen responsive B-box protein),CYP1A1 (cytochrome P450), CD36 (SR-B), SR-A (scavenger receptor A orMsr1), ABCA1 (ATP-binding cassette transporter A1), ABCG1 (ATP-bindingcassette transporter G1), LDLR (low-density lipoprotein receptor), NR1H3(nuclear receptor 1H3 or LXRα), NR1C3 (nuclear receptor 1C3 or PPARγ),SCD-1 (stearoyl-CoA desaturase 1) and NR⁴A1 (nuclear receptor 4A1 orNur77). F1C that can be characterized in this manner include the F1Cs inthe compound groups described above, e.g., one or more of16α-bromoepiandrosterone, 3β,16α-dihydroxyandrostane-17-one,3β,16α,17β-trihydroxyandrostane, 3α,16α,17β-trihydroxyandrostane,3β,17β-dihydroxy-16α-fluoroandrost-5-ene,3β,17β-dihydroxy-16α-fluoroandrost-1,5-diene,3β-hydroxy-17β-aminoandrost-5-ene,3β,7β-dihydroxy-17β-aminoandrost-5-ene,3β-hydroxy-7-oxo-17β-aminoandrost-5-ene,3α-hydroxy-17β-aminoandrost-5-ene, 3β-hydroxy-17β-aminoandrost-1,5-ene,3α-hydroxy-17β-aminoandrost-1,5-diene,3β-hydroxy-16α-fluoro-17β-aminoandrost-5-ene,3α-hydroxy-16α-fluoro-17β-aminoandrost-5-ene or3β-hydroxy-16α-fluoro-17β-aminoandrost-1,5-diene.

Example 22

Treatment of allograft rejection. The F1Cs are used as described hereinto treat, prevent or ameliorate unwanted immune responses in allografttransplantation. F1Cs in any of groups 1 through 52 or an analog of aF1C in any of groups 1 through 52 can be used in continuous orintermittent dosing protocols to ameliorate or to slow the progressionof rejection reactions in the host, such as hyperacute rejection, acuterejection or chronic rejection in allograft recipients in e.g., lung,heart, liver, kidney or bone marrow transplant recipients. Reduction ofsymptoms in kidney transplant recipients such as kidney enlargement ortenderness or increased serum creatinine levels, or decreased urineoutput are optionally monitored, e.g., for improvement or stabilizationof the symptom. The compounds are also used to reduce graft versus hostdisease in a similar manner.

To the extent not already indicated, it will be understood by those ofordinary skill in the art that any of the various specific embodiments,compounds or compositions described herein may be modified toincorporate other appropriate features, e.g., as shown in any other ofthe specific embodiments disclosed herein or in the cited references.

1. A compound having the structure

wherein the dotted lines are optional double bonds; R¹ is —OH or anester; R³ is —H, —OH, halogen or an ester; R⁴ in the β-configuration is—OH, an ester or an N-linked amino acid and R⁴ in the α-configuration is—H or optionally substituted alkynyl; R⁵ is —CH₃ or —C₂H₅; R^(10A) is—OH or R^(10A) is —H or —OH when R³ is —OH, halogen or an ester; andR^(10B) is a halogen.
 2. The compound of claim 1 wherein R⁵ is —CH₃ . 3.The compound of claim 2 wherein R^(10B) is —F.
 4. The compound of claim3 having the structure


5. The compound of claim 4 having the structure


6. The compound of claim 5 wherein R⁴ in the α-configuration is alkynyl.7. The compound of claim 5 wherein R⁴ in the α-configuration is —H. 8.The compound of claim 7 wherein R⁴ in the β-configuration is —OH or anN-linked amino acid.
 9. The compound of claim 6 wherein R¹ is —OH or—OC(O)CH₃ and R³ is —H or —OH.
 10. The compound of claim 7 wherein thecompound is 1α,3β, 17β-trihydroxy-4α-fluoroandrost-5-ene.